Cycloalkyl 3-oxopiperazine carboxamides and cycloheteroalkyl 3-oxopiperazine carboxamides as nav1.8 inhibitors

ABSTRACT

Novel compounds of structural formula (I), and the pharmaceutically acceptable salts thereof, are inhibitors of Na v 1.8 channel activity and may be useful in the treatment, prevention, management, amelioration, control and suppression of diseases mediated by Na v 1.8 channel activity. The compounds of Formula I may be useful in the treatment, prevention or management of pain disorders, cough disorders, acute itch disorders, and chronic itch disorders.

BACKGROUND OF THE INVENTION

Voltage-gated sodium channels (VGSC) mediate the selective influx ofsodium ions in excitable cells and play a central role in initiating andpropagating action potentials (Yu et al., Genome Biology 4:207 (2003)).Voltage-gated sodium channels are ubiquitous in the central andperipheral nervous system where they play a central role in theinitiation and propagation of action potentials, and also in skeletaland cardiac muscle where the action potential triggers cellularcontraction (Goldin et al., Ann N Y Acad Sci. 1999 Apr. 30; 868:38-50).Alterations in VGSC function or their expression can profoundly affectnormal cell excitability (Huang et al., J Neurosci. 2013 Aug. 28; 33(35):14087-97; Emery et al., J Neurosci. 2015 May 20; 35(20):7674-81;Kist et al., PLoS One. 2016 Sep. 6; 11(9):e0161789; and Schreiber etal., World J Diabetes. 2015 Apr. 15; 6(3):432-44).

Voltage-gated sodium channels are multimeric complexes characterized byone α-subunit, which forms an ion-conducting aqueous pore, and at leastone β-subunit that modifies the kinetics and voltage-dependence of thechannel gating. Nine different α-subunits have been identified andcharacterized in mammalian voltage-gated sodium channels, includingNa_(v)1.8, also known as SNS, PN3 or Na_(v)1.8 (Goldin et al., Neuron.2000 November; 28 (2):365-8).

Expression of sodium channels can be tissue specific. Na_(v)1.8voltage-gated sodium ion channels are expressed primarily in sensoryneurons, which are responsible for conveying information from theperiphery (e.g. skin, muscle and joints) to the central nervous systemvia the spinal cord. Sodium channels are integral to this process assodium channel activity is required for initiation and propagation ofaction potentials triggered by noxious stimuli (thermal, mechanical andchemical) activating peripheral nociceptors (Catterall et al., Nat ChemBiol. 2017 Apr. 13; 13(5):455-463). An increase in VGSC protein level atthe cell surface or an alteration in activity of the VGSC channels canresult in disease states such as migraine, neurodegeneration followingischemia, epilepsies, and chronic neuropathic and inflammatory painstates. Gain of function mutations in Nav1.7, Nav1.8, and Nav1.9manifest in a variety of pain syndromes where patients experiencespontaneous pain without an external stimulus (Bennett et al., LancetNeurol. 2014 Jun.; 13(6):587-99; Huang et al., J Neurosci. 2013 Aug. 28;33(35):14087-97; Kist et al., PLoS One. 2016 Sep. 6; 11(9):e0161789;Emery et al., J Neurosci. 2015 May 20; 35(20):7674-81; and Schreiber etal., World J Diabetes. 2015 Apr. 15; 6(3):432-44).

Na_(v)1.8 voltage-gated sodium ion channels are believed to play a rolein various maladies, including neuropathic pain, chronic itch, andinflammatory pain perception (Belkouch et al., J Neuroinflammation. 2014Mar. 7; 11:45; Coward et al., Pain. 2000 March; 85(1-2):41-50; Yiangouet al., FEBS Lett. 2000 Feb. 11; 467(2-3):249-52; Black et al., AnnNeurol. 2008 December; 64(6):644-53; Bird et al., Br J Pharmacol. 2015May; 172(10):2654-70; Liu et al., Neuron. 2010 Nov. 4; 68(3):543-56; andZhao et al., J Clin Invest. 2013).

Large portions of the voltage gated sodium ion channels are conservedamong the various subtypes; therefore there is a potential for producingserious side effects when utilizing therapeutic agents that do notdemonstrate subtype selectivity. Therefore, therapeutic agents suitablefor use in addressing nociception, cough, or itch disorders, requirespecificity in their action, for example, discriminating between actionupon Na_(v)1.5 sodium ion channels, thought to be important inregulation of cardiac function, and action upon Na_(v)1.8 sodium ionchannels, thought to be central in inflammatory nociception, or itch anddisorders arising from dysfunctional and/or upregulated Na_(v)1.8 sodiumion channels.

Accordingly, it is believed that inhibitors of Na_(v)1.8 voltage-gatedsodium ion channel activity may useful to treat or prevent diseases,disorders and conditions involving Na_(v)1.8 receptors and/or stemmingspecifically from dysfunction of Na_(v)1.8 voltage-gated sodium ionchannels (Han et al., J Neurol Neurosurg Psychiatry 2014 May;85(5):499-505), including but not limited to, migraine,neurodegeneration following ischemia, epilepsy, inflammatory pain,spontaneous pain, acute pain, preoperative pain, perioperative pain,post-operative pain, neuropathic pain, chronic itch, and itch disorders.

There remains a need for potent Na_(v)1.8 sodium ion channel activityinhibitors with selective activity for Na_(v)1.8 sodium ion channels. Asa result, the presently disclosed compounds are useful for the treatmentand prevention of diseases, disorders and conditions involving Na_(v)1.8receptors and Na_(v)1.8 voltage-gated sodium ion channels.

The role of Nav1.8 sodium ion channels is discussed in: Bennett et al.,Physical Medicine and Rehabilitation Clinics of North America, 2001,12(2):447-459; Meissner et al., Br J Sports Med. 2018 May;52(10):642-650; Legroux-Crespel et al., Neurology. 2016 Feb. 2;86(5):473-83; and Flaxman et al., Lancet, 380:2163-2196 (2012).

Compounds useful to treat Na_(v)1.8 sodium ion channel relatedconditions are disclosed in: ACS Med. Chem. Lett. 2015, 6, 650; BJP2015, 172, 2654; PNAS 2007, 104, 8520; J. Med. Chem. 2008, 51, 407; JPET2008, 324, 1204; and Neuropharmacology 2010, 59, 201.

Na_(v)1.8 compounds are also disclosed in: WO 2009/049180, WO2009/049181, WO 2009/049183, WO 2014/120808; WO 2014/120815; WO2014/120820; WO 2015/010065; and WO 2015/089361; WO 2017/209322; U.S.Pat. Nos. 8,519,137; 9,051,270; 9,108,903; 9,163,042; 9,783,501; WO2020/092667; WO2019/014352; WO2018/213426; U.S. Pat. No. 8,629,149; andWO2011/026240.

SUMMARY OF THE INVENTION

The present disclosure relates to novel compounds of structural formulaI:

and pharmaceutically acceptable salts, hydrates and solvates thereof.The compounds of structural formula I, and embodiments thereof, areinhibitors of Na_(v)1.8 sodium ion channel activity (or Na_(v)1.8inhibitors) and may be useful in the treatment and prevention ofdiseases, disorders and conditions mediated by Na_(v)1.8 sodium ionchannel activity, such as nociception, osteoarthritis, peripheralneuropathy, inherited erythromelalgia, multiple sclerosis, asthma, itch,atopy, allergic or contact dermatitis, renal failure, cholestasis,pruritus, acute itch, chronic itch, migraine, neurodegenerationfollowing ischemia, epilepsy, pain, inflammatory pain, spontaneous pain,acute pain, acute pain due to fractures, musculoskeletal damage,pancreatitis and renal colic, peri-operative pain, post-operative pain,neuropathic pain, postherpetic neuralgia, trigeminal neuralgia, diabeticneuropathy, chronic lower back pain, phantom limb pain, sciatica, paincaused by 2° or 3° burn injury, optic neuritis, pain resulting fromcancer and chemotherapy, chronic pelvic pain, pain syndromes, andcomplex regional pain syndromes. In one embodiment, the condition,disease or disorder is a pain disorder, an acute pain disorder orchronic pain disorder. In another embodiment, the condition, disease ordisorder is an acute pain disorder.

Also disclosed are pharmaceutical compositions comprising the compoundsof the present of structural formula I and a pharmaceutically acceptablecarrier.

Further disclosed are methods for the treatment, management, prevention,alleviation, amelioration, suppression or control of disorders,diseases, and conditions that may be responsive to inhibition ofNa_(v)1.8 sodium ion channel activity in a subject in need thereof byadministering the presently disclosed compounds and pharmaceuticalcompositions.

Further disclosed is the use of compounds of structural formula I formanufacture of a medicament useful in treating diseases, disorders andconditions that may be responsive to the inhibition of Na_(v)1.8 sodiumion channel activity.

Also disclosed is the treatment or prevention of these diseases,disorders and conditions by administering the disclosed compounds incombination with a therapeutically effective amount of another agentthat may be useful to treat the disease, disorder and condition. Furtherdescribed are processes for preparing the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

Provided arenovel compounds of structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein one of A and B isindependently selected from the group consisting of:

-   -   (1) aryl, and    -   (2) heteroaryl,        wherein aryl and heteroaryl are unsubstituted or substituted        with one to five substituents selected from R^(a), and        the other of A and B is independently selected from the group        consisting of:    -   (1) C₃₋₁₂cycloalkyl,    -   (2) C₂₋₁₁cycloheteroalkyl,    -   (3) —C₁₋₆alkyl-C₃₋₁₂cycloalkyl,    -   (4) —C₁₋₆alkyl-C₂₋₁₁cycloheteroalkyl,    -   (5) —C₁₋₆alkyl-O—C₃₋₁₂cycloalkyl, and    -   (6) —C₁₋₆alkyl-O—C₂₋₁₁cycloheteroalkyl,        wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted        or substituted with one to six substituents selected from R^(b);        R¹ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₂₋₆alkenyl,    -   (4) —C₂₋₆alkynyl,    -   (5) —C₃₋₆cycloalkyl,    -   (6) —C₂₋₆cycloheteroalkyl,    -   (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (8) —(CH₂)_(t)C(O)R^(j),    -   (9) —(CH₂)_(t)C(O)NR^(e)R^(j),    -   (10) —(CH₂)_(n)NR^(e)C(O)R^(j),    -   (11) —(CH₂)_(n)NR^(e)C(O)OR^(j),    -   (12) —(CH₂)_(n)NR^(e)C(O)N(R^(e))₂,    -   (13) —(CH₂)_(n)NR^(e)C(O)NR^(e)R^(j),    -   (14) —(CH₂)_(n)NR^(e)S(O)_(m)R^(j),    -   (15) —(CH₂)_(n)NR^(e)S(O)mN(R^(e))₂,    -   (16) —(CH₂)_(n)NR^(e)S(O)mNR^(e)R_(j), and    -   (17) —(CH₂)_(n)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(c);        R² is selected from the group consisting of:    -   (1) hydrogen,    -   (2) deuterium,    -   (3) —C₁₋₆alkyl,    -   (4) —C₂₋₆alkenyl,    -   (5) —C₂₋₆alkynyl,    -   (6) —C₃₋₆cycloalkyl,    -   (7) —C₂₋₆cycloheteroalkyl,    -   (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (9) —(CH₂)_(s)C(O)R^(j),    -   (10) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (18) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(d),        wherein R² and R³ and the carbon atoms they are connected to can        from a —C₃₋₅cycloalkyl ring, and wherein R² and R⁴ and the        carbon atoms they are connected to can from a —C₃₋₅cycloalkyl        ring;        R³ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) deuterium,    -   (3) —C₁₋₆alkyl,    -   (4) —C₂₋₆alkenyl,    -   (5) —C₂₋₆alkynyl,    -   (6) —C₃₋₆cycloalkyl,    -   (7) —C₂₋₆cycloheteroalkyl,    -   (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (9) —(CH₂)_(s)C(O)R^(j),    -   (10) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (18) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(d);        R⁴ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) deuterium,    -   (3) —C₁₋₆alkyl,    -   (4) —C₂₋₆alkenyl,    -   (5) —C₂₋₆alkynyl,    -   (6) —C₃₋₆cycloalkyl,    -   (7) —C₂₋₆cycloheteroalkyl,    -   (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (9) —(CH₂)_(s)C(O)R^(j),    -   (10) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (18) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(f), and        wherein R⁴ and R⁵ and the carbon atoms they are connected to can        from a —C₃₋₅cycloalkyl ring;        R⁵ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) deuterium,    -   (3) —C₁₋₆alkyl,    -   (4) —C₂₋₆alkenyl,    -   (5) —C₂₋₆alkynyl,    -   (6) —C₃₋₆cycloalkyl,    -   (7) —C₂₋₆cycloheteroalkyl,    -   (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (9) —(CH₂)_(s)C(O)R^(j),    -   (10) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (18) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(f), and        wherein R⁵ and R⁷ and the carbon atoms they are attached to may        form a 4-, 5- or 6-membered saturated ring;        R⁶ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) deuterium,    -   (3) —C₁₋₆alkyl,    -   (4) —C₂₋₆alkenyl,    -   (5) —C₂₋₆alkynyl,    -   (6) —C₃₋₆cycloalkyl,    -   (7) —C₂₋₆cycloheteroalkyl,    -   (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (9) —(CH₂)_(s)C(O)R^(j),    -   (10) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (18) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(g), and        wherein R⁶ and R⁷ and the carbon atoms they are connected to can        from a —C₃₋₅cycloalkyl ring;        R⁷ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) deuterium,    -   (3) —C₁₋₆alkyl,    -   (4) —C₂₋₆alkenyl,    -   (5) —C₂₋₆alkynyl,    -   (6) —C₃₋₆cycloalkyl,    -   (7) —C₂₋₆cycloheteroalkyl,    -   (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (9) —(CH₂)_(s)C(O)R^(j),    -   (10) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (18) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(g);        R⁸ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₃₋₆cycloalkyl, and    -   (4) —C₂₋₆cycloheteroalkyl,        wherein each alkyl, cycloalkyl and cycloheteroalkyl is        unsubstituted or substituted with one to five substituents        selected from halogen;        R⁹ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₂₋₆alkenyl, and    -   (4) —C₂₋₆alkynyl,        wherein each alkyl, alkenyl and alkynyl is unsubstituted or        substituted with one to five substituents selected from halogen;        each R^(a) is independently selected from the group consisting        of:    -   (1) CN,    -   (2) oxo,    -   (3) halogen,    -   (4) —S(O)₂C₁₋₆alkyl,    -   (5) —C₁₋₆alkyl,    -   (6) —C₂₋₆alkenyl,    -   (7) —C₂₋₆alkynyl,    -   (8) —C₃₋₆cycloalkyl,    -   (9) —C₂₋₆cycloheteroalkyl,    -   (10) aryl,    -   (11) heteroaryl,    -   (12) —C₁₋₆alkyl-aryl,    -   (13) —C₁₋₆alkyl-heteroaryl,    -   (14) —C₁₋₆alkyl-C₃₋₆cycloalkyl,    -   (15) —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl,    -   (16) —C₂₋₆alkenyl-C₃₋₆cycloalkyl,    -   (17) —C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl,    -   (18) —C₂₋₆alkenyl-aryl,    -   (19) —C₂₋₆alkenyl-heteroaryl,    -   (20) —C₂₋₆alkynyl-C₃₋₆cycloalkyl,    -   (21) —C₂₋₆alkynylC₂₋₆cycloheteroalkyl,    -   (22) —C₂₋₆alkynyl-aryl,    -   (23) —C₂₋₆alkynyl-heteroaryl,    -   (24) —OH,    -   (25) —(CH₂)_(p)—O—C₁₋₆alkyl,    -   (26) —(CH₂)_(p) —O—C₂₋₆alkenyl,    -   (27) —(CH₂)_(p) —O—C₂₋₆alkynyl,    -   (28) —(CH₂)_(p) —O—C₃₋₆cycloalkyl,    -   (29) —(CH₂)_(p) —O—C₂₋₆cycloheteroalkyl,    -   (30) —(CH₂)_(p) —O-aryl,    -   (31) —(CH₂)_(p) —O-heteroaryl,    -   (32) —OC₁₋₆alkyl-C₃₋₆cycloalkyl,    -   (33) —OC₁₋₆alkyl-C₂₋₆cycloheteroalkyl,    -   (34) —OC₁₋₆alkyl-aryl,    -   (35) —OC₁₋₆alkyl-heteroaryl,    -   (36) —S(O)_(r)R^(h),    -   (37) —C₁₋₆alkyl-S(O)_(r)R^(h),    -   (38) —N(R^(k))₂,    -   (39) —C(O)R^(L), and    -   (40) —NR^(k)R^(L),        wherein each R^(a) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and        —OC₁₋₆alkyl;        each R^(b) is independently selected from the group consisting        of:    -   (1) CN,    -   (2) oxo,    -   (3) halogen,    -   (4) —S(O)₂C₁₋₆alkyl,    -   (5) —C₁₋₆alkyl,    -   (6) —C₁₋₆alkenyl,    -   (7) —C₂₋₆alkynyl,    -   (8) —C₃₋₆cycloalkyl,    -   (9) —C₂₋₆cycloheteroalkyl,    -   (10) aryl,    -   (11) heteroaryl,    -   (12) —C₁₋₆alkyl-aryl,    -   (13) —C₁₋₆alkyl-heteroaryl,    -   (14) —C₁₋₆alkyl-C₃₋₆cycloalkyl,    -   (15) —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl,    -   (16) —C₂₋₆alkenyl-C₃₋₆cycloalkyl,    -   (17) —C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl,    -   (18) —C₂₋₆alkenyl-aryl,    -   (19) —C₂₋₆alkenyl-heteroaryl,    -   (20) —C₂₋₆alkynyl-C₃₋₆cycloalkyl,    -   (21) —C₂₋₆alkynyl-C₂₋₆cycloheteroalkyl,    -   (22) —C₂₋₆alkynyl-aryl,    -   (23) —C₂₋₆alkynyl-heteroaryl,    -   (24) —OH,    -   (25) —(CH₂)_(q)—O—C₁₋₆alkyl,    -   (26) —(CH₂)_(q)—O—C₂₋₆alkenyl,    -   (27) —(CH₂)_(q) —O—C₂₋₆alkynyl,    -   (28) —(CH₂)_(q) —O—C₃₋₆cycloalkyl,    -   (29) —(CH₂)_(q) —O—C₂₋₆cycloheteroalkyl,    -   (30) —(CH₂)_(q) —O-aryl,    -   (31) —(CH₂)_(q) —O-heteroaryl,    -   (32) —OC₁₋₆alkyl-C₃₋₆cycloalkyl,    -   (33) —OC₁₋₆alkyl-C₂₋₆cycloheteroalkyl,    -   (34) —OC₁₋₆alkyl-aryl,    -   (35) —OC₁₋₆alkyl-heteroaryl,    -   (36) —S(O)_(r)R^(i),    -   (37) —C₁₋₆alkyl-S(O)_(r)R^(i),    -   (38) —N(R^(k))₂,    -   (39) —C(O)R^(L), and    -   (40) —NR^(k)R^(L),        wherein each R^(b) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃,        CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl;        R^(c) is selected from:    -   (1) —C₁₋₆alkyl,    -   (2) OH,    -   (3) halogen, and    -   (4) —OC₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to three        halogens;        R^(d) is selected from:    -   (1) —C₁₋₆alkyl,    -   (2) OH,    -   (3) halogen, and    -   (4) —OC₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to three        halogens;        R^(e) is selected from:    -   (1) hydrogen, and    -   (2) C₁₋₆alkyl;        R^(f) is selected from:    -   (1) —C₁₋₆alkyl,    -   (2) OH,    -   (3) halogen, and    -   (4) —OC₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to three        halogens;        R^(g) is selected from:    -   (1) —C₁₋₆alkyl,    -   (2) OH,    -   (3) halogen, and    -   (4) —OC₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to three        halogens;        R^(h) is selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₆cycloalkyl,    -   (4) aryl, and    -   (5) heteroaryl;        R^(i) is selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₆cycloalkyl,    -   (4) aryl, and    -   (5) heteroaryl;        R^(j) is selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₆alkenyl,    -   (4) C₃₋₆alkynyl,    -   (5) C₃₋₆cycloalkyl,    -   (6) C₂₋₅cycloheteroalkyl,    -   (7) aryl, and    -   (8) heteroaryl;        R^(k) is selected from:    -   (1) hydrogen, and    -   (2) C₁₋₆alkyl;        R^(L) is selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₆cycloalkyl,    -   (4) aryl, and    -   (5) heteroaryl;        m is independently selected from 0, 1 and 2;        n is independently selected from 2, 3, 4, 5 and 6;        p is independently selected from 0, 1, 2 and 3;        q is independently selected from 0, 1, 2 and 3;        r is independently selected from 0, 1 and 2;        s is independently selected from 0, 1, 2, 3, 4, 5, and 6; and        t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

The present disclosure also provides novel compounds of structuralFormula I, or pharmaceutically acceptable salts thereof, wherein

one of A and B is independently selected from the group consisting of:

-   -   (1) aryl, and    -   (2) heteroaryl,        wherein aryl and heteroaryl are unsubstituted or substituted        with one to five substituents selected from R^(a), and        the other of A and B is independently selected from the group        consisting of:    -   (1) C₃₋₁₂cycloalkyl,    -   (2) C₂₋₁₁cycloheteroalkyl,    -   (3) —C₁₋₆alkyl-C₃₋₁₂cycloalkyl,    -   (4) —C₁₋₆alkyl-C₂₋₁₁cycloheteroalkyl,    -   (5) —C₁₋₆alkyl-O—C₃₋₁₂cycloalkyl, and    -   (6) —C₁₋₆alkyl-O—C₂₋₁₁cycloheteroalkyl,        wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted        or substituted with one to six substituents selected from R^(b);        R¹ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₂₋₆alkenyl,    -   (4) —C₂₋₆alkynyl,    -   (5) —C₃₋₆cycloalkyl,    -   (6) —C₂₋₆cycloheteroalkyl,    -   (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (8) —(CH₂)_(t)C(O)R^(j),    -   (9) —(CH₂)_(t)C(O)NR^(e)R^(j),    -   (10) —(CH₂)_(n)NR^(e)C(O)R^(j),    -   (11) —(CH₂)_(n)NR^(e)C(O)OR^(j),    -   (12) —(CH₂)_(n)NR^(e)C(O)N(R^(e))₂,    -   (13) —(CH₂)_(n)NR^(e)C(O)NR^(e)R^(j),    -   (14) —(CH₂)_(n)NR^(e)S(O)_(m)R^(j),    -   (15) —(CH₂)_(n)NR^(e)S(O)mN(R^(e))₂,    -   (16) —(CH₂)_(n)NR^(e)S(O)mNR^(e)R^(j), and    -   (17) —(CH₂)_(n)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(c);        R² is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₂₋₆alkenyl,    -   (4) —C₂₋₆alkynyl,    -   (5) —C₃₋₆cycloalkyl,    -   (6) —C₂₋₆cycloheteroalkyl,    -   (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (8) —(CH₂)_(s)C(O)R^(j),    -   (9) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (10) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (17) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(d),        wherein R² and R³ and the carbon atoms they are connected to can        from a —C₃₋₅cycloalkyl ring, and wherein R² and R⁴ and the        carbon atoms they are connected to can from a —C₃₋₅cycloalkyl        ring;        R³ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₂₋₆alkenyl,    -   (4) —C₂₋₆alkynyl,    -   (5) —C₃₋₆cycloalkyl,    -   (6) —C₂₋₆cycloheteroalkyl,    -   (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (8) —(CH₂)_(s)C(O)R^(j),    -   (9) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (10) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (17) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(d);        R⁴ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₂₋₆alkenyl,    -   (4) —C₂₋₆alkynyl,    -   (5) —C₃₋₆cycloalkyl,    -   (6) —C₂₋₆cycloheteroalkyl,    -   (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (8) —(CH₂)_(s)C(O)R^(j),    -   (9) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (10) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (17) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(f), and        wherein R⁴ and R⁵ and the carbon atoms they are connected to can        from a —C₃₋₅cycloalkyl ring;        R⁵ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₂₋₆alkenyl,    -   (4) —C₂₋₆alkynyl,    -   (5) —C₃₋₆cycloalkyl,    -   (6) —C₂₋₆cycloheteroalkyl,    -   (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (8) —(CH₂)_(s)C(O)R^(j),    -   (9) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (10) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (17) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(f), and        wherein R⁵ and R⁷ and the carbon atoms they are attached to may        form a 4-, 5- or 6-membered saturated ring;        R⁶ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₂₋₆alkenyl,    -   (4) —C₂₋₆alkynyl,    -   (5) —C₃₋₆cycloalkyl,    -   (6) —C₂₋₆cycloheteroalkyl,    -   (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (8) —(CH₂)_(s)C(O)R^(j),    -   (9) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (10) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (17) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(g), and        wherein R⁶ and R⁷ and the carbon atoms they are connected to can        from a —C₃₋₅cycloalkyl ring;        R⁷ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₂₋₆alkenyl,    -   (4) —C₂₋₆alkynyl,    -   (5) —C₃₋₆cycloalkyl,    -   (6) —C₂₋₆cycloheteroalkyl,    -   (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-,    -   (8) —(CH₂)_(s)C(O)R^(j),    -   (9) —(CH₂)_(s)C(O)NR^(e)R^(j),    -   (10) —(CH₂)_(s)NR^(e)C(O)R^(j),    -   (11) —(CH₂)_(s)NR^(e)C(O)OR^(j),    -   (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,    -   (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),    -   (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),    -   (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,    -   (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and    -   (17) —(CH₂)_(s)NR^(e)R^(j),        wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and        cycloheteroalkyl is unsubstituted or substituted with one to        five substituents selected from R^(g);        R⁸ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₃₋₆cycloalkyl, and    -   (4) —C₂₋₆cycloheteroalkyl,        wherein each alkyl, cycloalkyl and cycloheteroalkyl is        unsubstituted or substituted with one to five substituents        selected from halogen;        R⁹ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₂₋₆alkenyl, and    -   (4) —C₂₋₆alkynyl,        wherein each alkyl, alkenyl and alkynyl is unsubstituted or        substituted with one to five substituents selected from halogen;        each R^(a) is independently selected from the group consisting        of:    -   (1) CN,    -   (2) oxo,    -   (3) halogen,    -   (4) —S(O)₂C₁₋₆alkyl,    -   (5) —C₁₋₆alkyl,    -   (6) —C₂₋₆alkenyl,    -   (7) —C₂₋₆alkynyl,    -   (8) —C₃₋₆cycloalkyl,    -   (9) —C₂₋₆cycloheteroalkyl,    -   (10) aryl,    -   (11) heteroaryl,    -   (12) —C₁₋₆alkyl-aryl,    -   (13) —C₁₋₆alkyl-heteroaryl,    -   (14) —C₁₋₆alkyl-C₃₋₆cycloalkyl,    -   (15) —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl,    -   (16) —C₂₋₆alkenyl-C₃₋₆cycloalkyl,    -   (17) —C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl,    -   (18) —C₂₋₆alkenyl-aryl,    -   (19) —C₂₋₆alkenyl-heteroaryl,    -   (20) —C₂₋₆alkynyl-C₃₋₆cycloalkyl,    -   (21) —C₂₋₆alkynylC₂₋₆cycloheteroalkyl,    -   (22) —C₂₋₆alkynyl-aryl,    -   (23) —C₂₋₆alkynyl-heteroaryl,    -   (24) —OH,    -   (25) —(CH₂)_(p)—O—C₁₋₆alkyl,    -   (26) —(CH₂)_(p) —O—C₂₋₆alkenyl,    -   (27) —(CH₂)_(p) —O—C₂₋₆alkynyl,    -   (28) —(CH₂)_(p) —O—C₃₋₆cycloalkyl,    -   (29) —(CH₂)_(p) —O—C₂₋₆cycloheteroalkyl,    -   (30) —(CH₂)_(p) —O-aryl,    -   (31) —(CH₂)_(p) —O-heteroaryl,    -   (32) —OC₁₋₆alkyl-C₃₋₆cycloalkyl,    -   (33) —OC₁₋₆alkyl-C₂₋₆cycloheteroalkyl,    -   (34) —OC₁₋₆alkyl-aryl,    -   (35) —OC₁₋₆alkyl-heteroaryl,    -   (36) —S(O)_(r)R^(h),    -   (37) —C₁₋₆alkyl-S(O)_(r)R^(h),    -   (38) —N(R^(k))₂,    -   (39) —C(O)R^(L), and    -   (40) —NR^(k)R^(L),        wherein each R^(a) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and        —OC₁₋₆alkyl;        each R^(b) is independently selected from the group consisting        of:    -   (1) CN,    -   (2) oxo,    -   (3) halogen,    -   (4) —S(O)₂C₁₋₆alkyl,    -   (5) —C₁₋₆alkyl,    -   (6) —C₁₋₆alkenyl,    -   (7) —C₂₋₆alkynyl,    -   (8) —C₃₋₆cycloalkyl,    -   (9) —C₂₋₆cycloheteroalkyl,    -   (10) aryl,    -   (11) heteroaryl,    -   (12) —C₁₋₆alkyl-aryl,    -   (13) —C₁₋₆alkyl-heteroaryl,    -   (14) —C₁₋₆alkyl-C₃₋₆cycloalkyl,    -   (15) —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl,    -   (16) —C₂₋₆alkenyl-C₃₋₆cycloalkyl,    -   (17) —C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl,    -   (18) —C₂₋₆alkenyl-aryl,    -   (19) —C₂₋₆alkenyl-heteroaryl,    -   (20) —C₂₋₆alkynyl-C₃₋₆cycloalkyl,    -   (21) —C₂₋₆alkynyl-C₂₋₆cycloheteroalkyl,    -   (22) —C₂₋₆alkynyl-aryl,    -   (23) —C₂₋₆alkynyl-heteroaryl,    -   (24) —OH,    -   (25) —(CH₂)_(q)—O—C₁₋₆alkyl,    -   (26) —(CH₂)_(q)—O—C₂₋₆alkenyl,    -   (27) —(CH₂)_(q) —O—C₂₋₆alkynyl,    -   (28) —(CH₂)_(q) —O—C₃₋₆cycloalkyl,    -   (29) —(CH₂)_(q) —O—C₂₋₆cycloheteroalkyl,    -   (30) —(CH₂)_(q) —O-aryl,    -   (31) —(CH₂)_(q) —O-heteroaryl,    -   (32) —OC₁₋₆alkyl-C₃₋₆cycloalkyl,    -   (33) —OC₁₋₆alkyl-C₂₋₆cycloheteroalkyl,    -   (34) —OC₁₋₆alkyl-aryl,    -   (35) —OC₁₋₆alkyl-heteroaryl,    -   (36) —S(O)_(r)R^(i),    -   (37) —C₁₋₆alkyl-S(O)_(r)R^(i),    -   (38) —N(R^(k))₂,    -   (39) —C(O)R^(L), and    -   (40) —NR^(k)R^(L),        wherein each R^(b) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃,        CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl;        R^(c) is selected from:    -   (1) —C₁₋₆alkyl,    -   (2) OH,    -   (3) halogen, and    -   (4) —OC₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to three        halogens;        R^(d) is selected from:    -   (1) —C₁₋₆alkyl,    -   (2) OH,    -   (3) halogen, and    -   (4) —OC₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to three        halogens;        R^(e) is selected from:    -   (1) hydrogen, and    -   (2) C₁₋₆alkyl;        R^(f) is selected from:    -   (1) —C₁₋₆alkyl,    -   (2) OH,    -   (3) halogen, and    -   (4) —OC₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to three        halogens;        R^(g) is selected from:    -   (1) —C₁₋₆alkyl,    -   (2) OH,    -   (3) halogen, and    -   (4) —OC₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to three        halogens;        R^(h) is selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₆cycloalkyl,    -   (4) aryl, and    -   (5) heteroaryl;        R^(i) is selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₆cycloalkyl,    -   (4) aryl, and    -   (5) heteroaryl;        R^(j) is selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₆alkenyl,    -   (4) C₃₋₆alkynyl,    -   (5) C₃₋₆cycloalkyl,    -   (6) C₂₋₅cycloheteroalkyl,    -   (7) aryl, and    -   (8) heteroaryl;        R^(k) is selected from:    -   (1) hydrogen, and    -   (2) C₁₋₆alkyl;        R^(L) is selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₆cycloalkyl,    -   (4) aryl, and    -   (5) heteroaryl;        m is independently selected from 0, 1 and 2;        n is independently selected from 2, 3, 4, 5 and 6;        p is independently selected from 0, 1, 2 and 3;        q is independently selected from 0, 1, 2 and 3;        r is independently selected from 0, 1 and 2;        s is independently selected from 0, 1, 2, 3, 4, 5, and 6; and        t is independently selected from 0, 1, 2, 3, 4, 5, and 6.

The compounds of structural formula I have numerous embodiments, whichare summarized below. Included are the compounds as shown, and alsoindividual diastereoisomers, enantiomers, and epimers of the compounds,and mixtures of diastereoisomers and/or enantiomers thereof includingracemic mixtures.

In one embodiment, one of A and B is independently selected from thegroup consisting of: aryl and heteroaryl, wherein aryl and heteroarylare unsubstituted or substituted with one to five substituents selectedfrom R^(a), and the other of A and B is independently selected from thegroup consisting of: —C₃₋₁₂cycloalkyl, —C₂₋₁₁cycloheteroalkyl,—C₁₋₆alkyl-C₃₋₁₂cycloalkyl, —C₁₋₆alkyl-C₂₋₁₁cycloheteroalkyl,—C₁₋₆alkyl-O—C₃₋₁₂cycloalkyl, and —C₁₋₆alkyl-O—C₂₋₁₁cycloheteroalkyl,wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted orsubstituted with one to six substituents selected from R^(b).

In another embodiment, one of A and B is independently selected from thegroup consisting of: aryl, and heteroaryl, wherein aryl and heteroarylare unsubstituted or substituted with one to five substituents selectedfrom R^(a), and the other of A and B is independently selected from thegroup consisting of: —C₃₋₁₀cycloalkyl, —C₂₋₉cycloheteroalkyl,—C₁₋₆alkyl-C₃₋₁₂cycloalkyl, —C₁₋₆alkyl-C₂₋₁₁cycloheteroalkyl,—C₁₋₆alkyl-O—C₃₋₁₂cycloalkyl, and —C₁₋₆alkyl-O—C₂₋₁₁cycloheteroalkyl,wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted orsubstituted with one to six substituents selected from R^(b).

In another embodiment, one of A and B is independently selected from thegroup consisting of: aryl, and heteroaryl, wherein aryl and heteroarylare unsubstituted or substituted with one to five substituents selectedfrom R^(a), and the other of A and B is independently selected from thegroup consisting of: —C₃₋₁₂cycloalkyl, and —C₂₋₁₁cycloheteroalkyl,wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substitutedwith one to six substituents selected from R^(b).

In another embodiment, one of A and B is independently selected from thegroup consisting of: aryl, and heteroaryl, wherein aryl and heteroarylare unsubstituted or substituted with one to five substituents selectedfrom R^(a), and the other of A and B is independently selected from thegroup consisting of: —C₃₋₁₀cycloalkyl, and —C₂₋₉cycloheteroalkyl,wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substitutedwith one to six substituents selected from R^(b).

In another embodiment, one of A and B is independently selected from thegroup consisting of: phenyl, pyridine, and thiazole, wherein phenyl,pyridine and thiazole are unsubstituted or substituted with one to fivesubstituents selected from R^(a), and the other of A and B isindependently selected from the group consisting of: cyclopropane,cyclobutane, cyclopentane, cyclohexane, bicyclo[3.2.1]-octane,bicyclo[3.1.0]hexane, bicyclo[2.2.2]octane, spiro[2.5]octane,bicyclo[1.1.1]pentane, spiro[3.3]heptane, spiro[2.3]hexane,spiro[2.2]pentane, piperidine, tetrahydropyran, and chromane, whereinthe other of A and B is unsubstituted or substituted with one to sixsubstituents selected from R^(b).

In another embodiment, one of A and B is independently selected from thegroup consisting of phenyl, pyridine, and thiazole, wherein phenyl,pyridine and thiazole are unsubstituted or substituted with one to fivesubstituents selected from R^(a), and the other of A and B isindependently selected from the group consisting of: cyclopropane,cyclobutane, cyclopentane, cyclohexane, bicyclo[3.2.1]-octane,bicyclo[3.1.0]hexane, bicyclo[2.2.2]octane, spiro[2.5]octane,bicyclo[1.1.1]pentane, spiro[3.3]heptane, spiro[2.3]hexane,spiro[2.2]pentane, piperidine, and tetrahydropyran, wherein the other ofA and B is unsubstituted or substituted with one to six substituentsselected from R^(b).

In another embodiment, one of A and B is independently selected from thegroup consisting of: phenyl, and pyridine, wherein phenyl and pyridineare unsubstituted or substituted with one to four substituents selectedfrom R^(a), and

the other of A and B is independently selected from the group consistingof cyclobutane, cyclohexane, tetrahydropyran, and chromane, whereincyclobutane, cyclohexane and tetrahydropyran are unsubstituted orsubstituted with one to six substituents selected from R^(b).

In another embodiment, one of A and B is independently selected from thegroup consisting of: phenyl, and pyridine, wherein phenyl and pyridineare unsubstituted or substituted with one to four substituents selectedfrom R^(a), and

the other of A and B is independently selected from the group consistingof cyclobutane, cyclohexane, and tetrahydropyran, wherein cyclobutane,cyclohexane and tetrahydropyran are unsubstituted or substituted withone to six substituents selected from R^(b).

In one embodiment, A is selected from the group consisting of aryl, andheteroaryl, wherein aryl and heteroaryl are unsubstituted or substitutedwith one to five substituents selected from R^(a).

In another embodiment, A is selected from the group consisting of:phenyl, pyridine, and thiazole, wherein phenyl, pyridine and thiazoleare unsubstituted or substituted with one to five substituents selectedfrom R^(a).

In another embodiment, A is selected from the group consisting ofphenyl, and pyridine, wherein phenyl and pyridine are unsubstituted orsubstituted with one to four substituents selected from R^(a).

In one embodiment, B is independently selected from the group consistingof: —C₃₋₁₂cycloalkyl, —C₂₋₁₁cycloheteroalkyl,—C₁₋₆alkyl-C₃₋₁₂cycloalkyl, —C₁₋₆alkyl-C₂₋₁₁cycloheteroalkyl,—C₁₋₆alkyl-O—C₃₋₁₂cycloalkyl, and —C₁₋₆alkyl-O—C₂₋₁₁cycloheteroalkyl,wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted orsubstituted with one to six substituents selected from R^(b).

In another embodiment, B is independently selected from the groupconsisting of: —C₃₋₁₀cycloalkyl, —C₂₋₉cycloheteroalkyl,—C₁₋₆alkyl-C₃₋₁₂cycloalkyl, —C₁₋₆alkyl-C₂₋₁₁cycloheteroalkyl,—C₁₋₆alkyl-O—C₃₋₁₂cycloalkyl, and —C₁₋₆alkyl-O—C₂₋₁₁cycloheteroalkyl,wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted orsubstituted with one to six substituents selected from R^(b).

In another embodiment, B is independently selected from the groupconsisting of: —C₃₋₁₂cycloalkyl, and —C₂₋₁₁cycloheteroalkyl, whereincycloalkyl and cycloheteroalkyl are unsubstituted or substituted withone to six substituents selected from R^(b).

In another embodiment, B is independently selected from the groupconsisting of: —C₃₋₁₀cycloalkyl, and —C₂₋₉cycloheteroalkyl, whereincycloalkyl and cycloheteroalkyl are unsubstituted or substituted withone to six substituents selected from R^(b).

In another embodiment, B is independently selected from the groupconsisting of: cyclopropane, cyclobutane, cyclopentane, cyclohexane,bicyclo[3.2.1]octane, bicyclo[3.1.0]hexane, bicyclo[2.2.2]octane,spiro[2.5]octane, bicyclo[1.1.1]pentane, spiro[3.3]heptane,spiro[2.3]hexane, spiro[2.2]pentane, piperidine, tetrahydropyran, andchromane, wherein B is unsubstituted or substituted with one to sixsubstituents selected from R^(b).

In another embodiment, B is independently selected from the groupconsisting of: cyclopropane, cyclobutane, cyclopentane, cyclohexane,bicyclo[3.2.1]octane, bicyclo[3.1.0]hexane, bicyclo[2.2.2]octane,spiro[2.5]octane, bicyclo[1.1.1]pentane, spiro[3.3]heptane,spiro[2.3]hexane, spiro[2.2]pentane, piperidine, and tetrahydropyran,wherein B is unsubstituted or substituted with one to six substituentsselected from R^(b).

In another embodiment, B is independently selected from the groupconsisting of: cyclobutane, cyclohexane, and tetrahydropyran, whereincyclobutane, cyclohexane, tetrahydropyran, and chromane areunsubstituted or substituted with one to six substituents selected fromR^(b).

In another embodiment, B is independently selected from the groupconsisting of: cyclobutane, cyclohexane, and tetrahydropyran, whereincyclobutane, cyclohexane and tetrahydropyran are unsubstituted orsubstituted with one to six substituents selected from R^(b).

In one embodiment, R¹ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(t)C(O)R^(j),—(CH₂)_(t)C(O)NR^(e)R^(j), —(CH₂)_(n)NR^(e)C(O)R^(j),—(CH₂)_(n)NR^(e)C(O)OR^(j), —(CH₂)_(n)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(n)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(n)NR^(e)S(O)_(m)R^(j),—(CH₂)_(n)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(n)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(n)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with oneto five substituents selected from R^(c).

In another embodiment, R¹ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, and—C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyland cycloheteroalkyl is unsubstituted or substituted with one to fivesubstituents selected from R^(c).

In another embodiment, R¹ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein each alkyl andcycloalkyl is unsubstituted or substituted with one to five substituentsselected from R^(c). In a class of this embodiment, R¹ is selected fromthe group consisting of: hydrogen, —CH₃, and cyclopropyl, wherein eachalkyl and cycloalkyl is unsubstituted or substituted with one to threesubstituents selected from R^(c).

In another embodiment, R¹ is selected from the group consisting of:hydrogen, and —C₁₋₆alkyl, wherein each alkyl is unsubstituted orsubstituted with one to five substituents selected from R^(c). In aclass of this embodiment, R¹ is selected from the group consisting of:hydrogen, and —CH₃, wherein —CH₃ is unsubstituted or substituted withone to three substituents selected from R^(c). In another class of thisembodiment, R¹ is hydrogen.

In another embodiment, R¹ is —C₁₋₆alkyl, wherein alkyl is unsubstitutedor substituted with one to five substituents selected from R^(c). In aclass of this embodiment, R¹ is —CH₃, wherein —CH₃ is unsubstituted orsubstituted with one to three substituents selected from R^(c).

In one embodiment, R² is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R^(j),—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(d), wherein R² and R³ and thecarbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring, andwherein R² and R⁴ and the carbon atoms they are connected to can from a—C₃₋₅cycloalkyl ring.

In another embodiment, R² is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R,—(CH₂)_(s)NR^(e)C(O)OR, —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(d), wherein R² and R³ and thecarbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring, andwherein R² and R⁴ and the carbon atoms they are connected to can from a—C₃₋₅cycloalkyl ring.

In another embodiment, R² is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR,—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(d), and wherein R² and R³ and the carbon atoms they are connected tocan from a —C₃₋₅cycloalkyl ring.

In another embodiment, R² is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R^(j),—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(d), and wherein R² and R³ andthe carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring.

In another embodiment, R² is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR^(j),—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(d), and wherein R² and R⁴ and the carbon atoms they are connected tocan from a —C₃₋₅cycloalkyl ring.

In another embodiment, R² is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R^(j),—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(d), and wherein R² and R⁴ andthe carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring.

In another embodiment, R² is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR^(j),—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(d).

In another embodiment, R² is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R,—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(d).

In another embodiment, R² is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, and —C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(d).

In another embodiment, R² is selected from the group consisting ofhydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, and—C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,and cycloheteroalkyl is unsubstituted or substituted with one to fivesubstituents selected from R^(d).

In another embodiment, R² is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein each alkyland cycloalkyl is unsubstituted or substituted with one to fivesubstituents selected from R^(d). In a class of this embodiment, R² isselected from the group consisting of: hydrogen, deuterium, —CH₃, andcyclopropyl, wherein each alkyl and cycloalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(d).

In another embodiment, R² is selected from the group consisting ofhydrogen, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein each alkyl andcycloalkyl is unsubstituted or substituted with one to five substituentsselected from R^(d). In a class of this embodiment, R² is selected fromthe group consisting of: hydrogen, —CH₃, and cyclopropyl, wherein eachalkyl and cycloalkyl is unsubstituted or substituted with one to fivesubstituents selected from R^(d).

In another embodiment, R² is selected from the group consisting of:hydrogen, deuterium, and —C₁₋₆alkyl, wherein each alkyl and cycloalkylis unsubstituted or substituted with one to five substituents selectedfrom R^(d). In a class of this embodiment, R² is selected from the groupconsisting of: hydrogen, deuterium, and —CH₃, wherein each —CH₃ isunsubstituted or substituted with one to three substituents selectedfrom R^(d). In another embodiment, R² is hydrogen. In anotherembodiment, R² is deuterium.

In another embodiment, R² is selected from the group consisting ofhydrogen, and —C₁₋₆alkyl, wherein each alkyl and cycloalkyl isunsubstituted or substituted with one to five substituents selected fromR^(d). In a class of this embodiment, R² is selected from the groupconsisting of: hydrogen, and —CH₃, wherein each —CH₃ is unsubstituted orsubstituted with one to three substituents selected from R^(d).

In another embodiment, R² is —C₁₋₆alkyl, wherein each alkyl andcycloalkyl is unsubstituted or substituted with one to five substituentsselected from R^(d). In a class of this embodiment, R² is —CH₃, wherein—CH₃ is unsubstituted or substituted with one to three substituentsselected from R^(d).

In one embodiment, R³ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR^(j),—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(d).

In another embodiment, R³ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R^(j),—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(d).

In another embodiment, R³ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, and —C₂₋₆cyclo-heteroalkyl, wherein each alkyl,alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(d).

In another embodiment, R³ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, and—C₂₋₆cyclo-heteroalkyl, wherein each alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(d).

In another embodiment, R³ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein eachalkyl, and cycloalkyl is unsubstituted or substituted with one to fivesubstituents selected from R^(d). In a class of this embodiment, R³ isselected from the group consisting of: hydrogen, deuterium, —CH₃, andcyclopropyl, wherein cyclopropyl is unsubstituted or substituted withone to three substituents selected from R^(d).

In another embodiment, R³ is selected from the group consisting ofhydrogen, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein each alkyl, andcycloalkyl is unsubstituted or substituted with one to five substituentsselected from R^(d). In a class of this embodiment, R³ is selected fromthe group consisting of hydrogen, —CH₃, and cyclopropyl, whereincyclopropyl is unsubstituted or substituted with one to threesubstituents selected from R^(d).

In another embodiment, R³ is selected from the group consisting of:hydrogen, deuterium, and —C₁₋₆alkyl, wherein each alkyl is unsubstitutedor substituted with one to five substituents selected from R^(d). In aclass of this embodiment, R³ is selected from the group consisting of:hydrogen, deuterium, and —CH₃, wherein CH₃ is unsubstituted orsubstituted with one to three substituents selected from R^(d). Inanother class of this embodiment, R³ is hydrogen. In another class ofthis embodiment, R³ is deuterium.

In another embodiment, R³ is selected from the group consisting of:hydrogen, and —C₁₋₆alkyl, wherein each alkyl is unsubstituted orsubstituted with one to five substituents selected from R^(d). In aclass of this embodiment, R³ is selected from the group consisting ofhydrogen, and —CH₃, wherein CH₃ is unsubstituted or substituted with oneto three substituents selected from R^(d). In another class of thisembodiment, R³ is hydrogen.

In another embodiment, R³ is —C₁₋₆alkyl, wherein each alkyl isunsubstituted or substituted with one to five substituents selected fromR^(d). In a class of this embodiment, R³ is —CH₃, wherein —CH₃ isunsubstituted or substituted with one to three substituents selectedfrom R^(d).

In one embodiment, R⁴ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR^(j),—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(f), and wherein R⁴ and R⁵ and the carbon atoms they are connected tocan from a —C₃₋₅cycloalkyl ring.

In another embodiment, R⁴ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R,—(CH₂)_(s)NR^(e)C(O)OR, —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(f), and wherein R⁴ and R⁵ andthe carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring.

In another embodiment, R⁴ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR^(j),—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(f).

In another embodiment, R⁴ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R,—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(f).

In another embodiment, R⁴ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, and —C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(f).

In another embodiment, R⁴ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, and—C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,and cycloheteroalkyl is unsubstituted or substituted with one to fivesubstituents selected from R^(f).

In another embodiment, R⁴ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein each alkyland cycloalkyl is unsubstituted or substituted with one to fivesubstituents selected from R^(f). In a class of this embodiment, R⁴ isselected from the group consisting of: hydrogen, deuterium, —CH₃, andcyclopropyl, wherein each —CH₃ and cyclopropyl is unsubstituted orsubstituted with one to three substituents selected from R^(f).

In another embodiment, R⁴ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein each alkyl andcycloalkyl is unsubstituted or substituted with one to five substituentsselected from R^(f). In a class of this embodiment, R⁴ is selected fromthe group consisting of: hydrogen, —CH₃, and cyclopropyl, wherein each—CH₃ and cyclopropyl is unsubstituted or substituted with one to threesubstituents selected from R^(f).

In another embodiment, R⁴ is selected from the group consisting of:hydrogen, deuterium, and —C₁₋₆alkyl, wherein each alkyl is unsubstitutedor substituted with one to five substituents selected from R^(f). In aclass of this embodiment, R⁴ is hydrogen. In another class of thisembodiment, R⁴ is deuterium. In another class of this embodiment, R⁴ is—CH₃, wherein —CH₃ is unsubstituted or substituted with one to threesubstituents selected from R^(f).

In another embodiment, R⁴ is selected from the group consisting of:hydrogen, and —C₁₋₆alkyl, wherein each alkyl is unsubstituted orsubstituted with one to five substituents selected from R^(f). In aclass of this embodiment, R⁴ is hydrogen. In another class of thisembodiment, R⁴ is —CH₃, wherein —CH₃ is unsubstituted or substitutedwith one to three substituents selected from R^(f).

In another embodiment, R⁴ is —C₁₋₆alkyl, wherein each alkyl isunsubstituted or substituted with one to five substituents selected fromR^(f). In a class of this embodiment, R⁴ is —CH₃, wherein —CH₃ isunsubstituted or substituted with one to three substituents selectedfrom R^(f).

In one embodiment, R⁵ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR^(j),—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(f), and wherein R⁵ and R⁷ and the carbon atoms they are attached tomay form a 4-, 5- or 6-membered saturated ring.

In another embodiment, R⁵ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R^(j),—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(f), and wherein R⁵ and R⁷ andthe carbon atoms they are attached to may form a 4-, 5- or 6-memberedsaturated ring.

In another embodiment, R⁵ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR^(j),—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(f), and wherein R⁵ and R⁷ and the carbon atoms they are attached tomay form a 5-membered saturated ring.

In another embodiment, R⁵ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R^(j),—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(f), and wherein R⁵ and R⁷ andthe carbon atoms they are attached to may form a 5-membered saturatedring.

In another embodiment, R⁵ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₁₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR^(j),—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(f).

In another embodiment, R⁵ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₁₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R,—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(f).

In another embodiment, R⁵ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, and —C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(f).

In another embodiment, R⁵ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, and—C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,and cycloheteroalkyl is unsubstituted or substituted with one to fivesubstituents selected from R^(f).

In another embodiment, R⁵ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein alkyl andcycloalkyl is unsubstituted or substituted with one to five substituentsselected from R^(f). In a class of this embodiment, R⁵ is selected fromthe group consisting of: hydrogen, —CH₃, and cyclopropyl, wherein eachCH₃ and cyclopropyl is unsubstituted or substituted with one to threesubstituents selected from R^(f).

In another embodiment, R⁵ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein alkyl and cycloalkylis unsubstituted or substituted with one to five substituents selectedfrom R^(f). In a class of this embodiment, R⁵ is selected from the groupconsisting of: hydrogen, —CH₃, and cyclopropyl, wherein each CH₃ andcyclopropyl is unsubstituted or substituted with one to threesubstituents selected from R^(f).

In another embodiment, R⁵ is selected from the group consisting of:hydrogen, deuterium, and —C₁₋₆alkyl, wherein alkyl is unsubstituted orsubstituted with one to five substituents selected from R^(f). Inanother embodiment, R⁵ is hydrogen. In another embodiment, R⁵ isdeuterium.

In another embodiment, R⁵ is selected from the group consisting of:hydrogen, and —C₁₋₆alkyl, wherein alkyl is unsubstituted or substitutedwith one to five substituents selected from R^(f). In anotherembodiment, R⁵ is hydrogen.

In another embodiment, R⁵ is —C₁₋₆alkyl, wherein alkyl is unsubstitutedor substituted with one to five substituents selected from R^(f). In aclass of this embodiment, R⁵ is —CH₃, wherein —CH₃ is unsubstituted orsubstituted with one to three substituents selected from R^(f).

In one embodiment, R⁶ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR^(j),—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(g), and wherein R⁶ and R⁷ and the carbon atoms they are connected tocan from a —C₃₋₅cycloalkyl ring.

In another embodiment, R⁶ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R^(j),—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(g), and wherein R⁶ and R⁷ andthe carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring.

In another embodiment, R⁶ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR^(j),—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(g).

In another embodiment, R⁶ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R^(j),—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(g).

In another embodiment, R⁶ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, and —C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl,alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(g). Inanother embodiment, R⁶ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, and —C₃₋₆cycloalkyl,wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(g).

In another embodiment, R⁶ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, and—C₂₋₆cycloheteroalkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,and cycloheteroalkyl is unsubstituted or substituted with one to fivesubstituents selected from R^(g). In another embodiment, R⁶ is selectedfrom the group consisting of: hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, and —C₃₋₆cycloalkyl, wherein each alkyl, alkenyl, alkynyl,and cycloalkyl is unsubstituted or substituted with one to fivesubstituents selected from R^(g).

In another embodiment, R⁶ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein alkyl andcycloalkyl is unsubstituted or substituted with one to five substituentsselected from R^(g). In a class of this embodiment, R⁶ is selected fromthe group consisting of: hydrogen, deuterium, —CH₃, —CF₃, —CH₂CH₃,—CH₂F, —CH₂OH, and cyclopropyl, wherein cyclopropyl is unsubstituted orsubstituted with one to five substituents selected from R^(g). Inanother class of this embodiment, R⁶ is selected from the groupconsisting of hydrogen, deuterium, —CH₃, and cyclopropyl, whereincyclopropyl is unsubstituted or substituted with one to fivesubstituents selected from R^(g).

In another embodiment, R⁶ is selected from the group consisting ofhydrogen, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein alkyl and cycloalkylis unsubstituted or substituted with one to five substituents selectedfrom R^(g). In a class of this embodiment, R⁶ is selected from the groupconsisting of hydrogen, —CH₃, —CH₂CH₃, —CH₂F, and cyclopropyl, whereincyclopropyl is unsubstituted or substituted with one to fivesubstituents selected from R^(g). In another class of this embodiment,R⁶ is selected from the group consisting of hydrogen, —CH₃, andcyclopropyl, wherein cyclopropyl is unsubstituted or substituted withone to five substituents selected from R^(g).

In another embodiment, R⁶ is selected from the group consisting of:hydrogen, deuterium, and C₁₋₆alkyl, wherein alkyl is unsubstituted orsubstituted with one to five substituents selected from R^(g). In aclass of this embodiment, R⁶ is selected from the group consisting of:hydrogen, deuterium, —CH₃, —CF₃, —CH₂CH₃, —CH₂OH, and —CH₂F. In anotherclass of this embodiment, R⁶ is selected from the group consisting of:hydrogen, and —CH₃. In another embodiment, R⁶ is hydrogen.

In another embodiment, R⁶ is selected from the group consisting of:hydrogen, and —C₁₋₆alkyl, wherein alkyl is unsubstituted or substitutedwith one to five substituents selected from R^(g). In a class of thisembodiment, R⁶ is selected from the group consisting of: hydrogen, —CH₃,—CH₂CH₃, and —CH₂F. In another class of this embodiment, R⁶ is selectedfrom the group consisting of: hydrogen, and —CH₃. In another embodiment,R⁶ is hydrogen.

In another embodiment, R⁶ is selected from the group consisting of:—C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tofive substituents selected from R^(g). In a class of this embodiment, R⁶is selected from the group consisting of —CH₃, —CH₂CH₃, and —CH₂F. Inanother class of this embodiment, R⁶ is —CH₃.

In one embodiment, R⁷ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-,—(CH₂)_(s)C(O)R^(j), —(CH₂)_(s)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)C(O)R^(j), —(CH₂)_(s)NR^(e)C(O)OR^(j),—(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j),—(CH₂)_(s)NR^(e)S(O)_(m)R^(j), —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂,—(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and —(CH₂)_(s)NR^(e)R^(j), whereineach CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl isunsubstituted or substituted with one to five substituents selected fromR^(g).

In another embodiment, R⁷ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl-, —(CH₂)_(s)C(O)R^(j),—(CH₂)_(s)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)C(O)R^(j),—(CH₂)_(s)NR^(e)C(O)OR^(j), —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂,—(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), —(CH₂)_(s)NR^(e)S(O)_(m)R^(j),—(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and—(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl,cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted withone to five substituents selected from R^(g).

In another embodiment, R⁷ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₆cycloalkyl, and —C₂₋₆cycloheteroalkyl, wherein alkyl, alkenyl,alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(g).

In another embodiment, R⁷ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, and—C₂₋₆cycloheteroalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, andcycloheteroalkyl is unsubstituted or substituted with one to fivesubstituents selected from R^(g).

In another embodiment, R⁷ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, and—C₃₋₆cycloalkyl, wherein alkyl, alkenyl, alkynyl, and cycloalkyl isunsubstituted or substituted with one to five substituents selected fromR^(g).

In another embodiment, R⁷ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, and —C₃₋₆cycloalkyl,wherein alkyl, alkenyl, alkynyl, and cycloalkyl is unsubstituted orsubstituted with one to five substituents selected from R^(g).

In another embodiment, R⁷ is selected from the group consisting of:hydrogen, deuterium, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein alkyl, andcycloalkyl is unsubstituted or substituted with one to five substituentsselected from R^(g). In a class of this embodiment, R⁷ is selected fromthe group consisting of: hydrogen, deuterium, —CH₃, —CF₃, —CH₂CH₃,—CH₂F, —CH₂OH and cyclopropyl, wherein cyclopropyl is unsubstituted orsubstituted with one to five substituents selected from R^(g). In aclass of this embodiment, R⁷ is selected from the group consisting of:hydrogen, deuterium, —CH₃, —CH₂CH₃, —CH₂F and cyclopropyl, whereincyclopropyl is unsubstituted or substituted with one to fivesubstituents selected from R^(g). In another class of this embodiment,R⁷ is selected from the group consisting of: hydrogen, deuterium, —CH₃,and cyclopropyl, wherein cycloalkyl is unsubstituted or substituted withone to five substituents selected from R^(g). In another embodiment, R⁷is hydrogen. In another embodiment, R⁷ is deuterium.

In another embodiment, R⁷ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, and —C₃₋₆cycloalkyl, wherein alkyl, and cycloalkylis unsubstituted or substituted with one to five substituents selectedfrom R^(g). In a class of this embodiment, R⁷ is selected from the groupconsisting of: hydrogen, —CH₃, —CH₂CH₃, —CH₂F and cyclopropyl, whereincyclopropyl is unsubstituted or substituted with one to fivesubstituents selected from R^(g). In another class of this embodiment,R⁷ is selected from the group consisting of: hydrogen, —CH₃, andcyclopropyl, wherein cycloalkyl is unsubstituted or substituted with oneto five substituents selected from R^(g). In another embodiment, R⁷ ishydrogen.

Here In one embodiment, R⁸ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, and —C₂₋₆cycloheteroalkyl,wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted orsubstituted with one to five substituents selected from halogen.

In another embodiment, R⁸ is selected from the group consisting of:hydrogen, and —C₁₋₆alkyl, wherein alkyl is unsubstituted or substitutedwith one to five substituents selected from halogen. In anotherembodiment, R⁸ is hydrogen.

In another embodiment, R⁸ is —C₁₋₆alkyl, wherein alkyl is unsubstitutedor substituted with one to five substituents selected from halogen.

In one embodiment, R⁹ is selected from the group consisting of:hydrogen, —C₁₋₆alkyl, —C₂₋₆alkenyl, and —C₂₋₆alkynyl, wherein eachalkyl, alkenyl and alkynyl is unsubstituted or substituted with one tofive substituents selected from halogen.

In another embodiment, R⁹ is selected from the group consisting of:hydrogen, and —C₁₋₆alkyl, wherein alkyl is unsubstituted or substitutedwith one to five substituents selected from halogen. In a class of thisembodiment, R⁹ is selected from the group consisting of: hydrogen, andCH₃. In another embodiment, R⁹ is hydrogen.

In another embodiment, R⁹ is —C₁₋₆alkyl, wherein alkyl is unsubstitutedor substituted with one to five substituents selected from halogen. In aclass of this embodiment, R⁹ is —C₁₋₆alkyl, CH₃.

In one embodiment, each R^(a) is independently selected from the groupconsisting of: CN, oxo, halogen, —S(O)₂C₁₋₆alkyl, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl,aryl, heteroaryl, —C₁₋₆alkyl-aryl, —C₁₋₆alkyl-heteroaryl,—C₁₋₆alkyl-C₃₋₆cycloalkyl, —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl,—C₂₋₆alkenyl-C₃₋₆cycloalkyl, —C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl,—C₂₋₆alkenyl-aryl, —C₂₋₆alkenyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₆cycloalkyl,—C₂₋₆alkynylC₂₋₆cycloheteroalkyl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —OH, —(CH₂)_(p)—O—C₁₋₆alkyl, —(CH₂)_(p)—O—C₂₋₆alkenyl, —(CH₂)_(p) —O—C₂₋₆alkynyl, —(CH₂)_(p) —O—C₃₋₆cycloalkyl,—(CH₂)_(p) —O—C₂₋₆cycloheteroalkyl, —(CH₂)_(p) —O-aryl, —(CH₂)_(p)—O-heteroaryl, —OC₁₋₆alkyl-C₃₋₆cycloalkyl,—OC₁₋₆alkyl-C₂₋₆cycloheteroalkyl, —OC₁₋₆alkyl-aryl,—OC₁₋₆alkyl-heteroaryl, —S(O)_(r)R^(h), —C₁₋₆alkyl-S(O)_(r)R^(h),—N(R^(k))₂, —C(O)R^(L), and —NR^(k)R^(L), wherein each R^(a) isunsubstituted or substituted with one to six substituents selected fromhalogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl.

In another embodiment, each R^(a) is independently selected from thegroup consisting of: CN, oxo, halogen, —S(O)₂C₁₋₆alkyl, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl,aryl, heteroaryl, —C₁₋₆alkyl-aryl, —C₁₋₆alkyl-heteroaryl,—C₁₋₆alkyl-C₃₋₆cycloalkyl, —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl, —OH,—(CH₂)_(p)—O—C₁₋₆alkyl, —(CH₂)_(p) —O—C₂₋₆alkenyl, —(CH₂)_(p)—O—C₂₋₆alkynyl, —(CH₂)_(p) —O—C₃₋₆cycloalkyl, —(CH₂)_(p)—O—C₂₋₆cycloheteroalkyl, —(CH₂)_(p) —O-aryl, and —(CH₂)_(p)—O-heteroaryl, wherein each R^(a) is unsubstituted or substituted withone to six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and—OC₁₋₆alkyl.

In another embodiment, each R^(a) is independently selected from thegroup consisting of: CN, oxo, halogen, —S(O)₂C₁₋₆alkyl, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl,aryl, heteroaryl, —OH, —O—C₁₋₆alkyl, —O—C₂₋₆alkenyl, —O—C₂₋₆alkynyl,—O—C₃₋₆cycloalkyl, —O—C₂₋₆cycloheteroalkyl, —O-aryl, and —O-heteroaryl,wherein each R^(a) is unsubstituted or substituted with one to sixsubstituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl.

In another embodiment, each R^(a) is independently selected from thegroup consisting of CN, oxo, halogen, —S(O)₂C₁₋₆alkyl, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, aryl, heteroaryl,—OH, —O—C₁₋₆alkyl, —O—C₃₋₆cycloalkyl, and —O—C₂₋₆cycloheteroalkyl,wherein each R^(a) is unsubstituted or substituted with one to sixsubstituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl.

In another embodiment, each R^(a) is independently selected from thegroup consisting of CN, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, aryl, heteroaryl, —O—C₁₋₆alkyl,—O—C₃₋₆cycloalkyl, and —O—C₂₋₆cycloheteroalkyl, wherein each R^(a) isunsubstituted or substituted with one to six substituents selected fromhalogen, CF₃, OH, C₁₋₆alkyl, and OC₁₋₆alkyl.

In another embodiment, each R^(a) is independently selected from thegroup consisting of CN, halogen, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—C₂₋₆cycloheteroalkyl, —O—C₁₋₆alkyl, —O—C₃₋₆cycloalkyl, and—O—C₂₋₆cycloheteroalkyl, wherein each R^(a) is unsubstituted orsubstituted with one to six substituents selected from halogen, CF₃, OH,C₁₋₆alkyl, and OC₁₋₆alkyl.

In another embodiment, each R^(a) is independently selected from thegroup consisting of CN, halogen, —C₁₋₆alkyl, and —O—C₁₋₆alkyl, whereineach R^(a) is unsubstituted or substituted with one to six substituentsselected from halogen, CF₃, OH, C₁₋₆alkyl, and OC₁₋₆alkyl.

In another embodiment, each R^(a) is independently selected from thegroup consisting of halogen, —C₁₋₆alkyl, and —O—C₁₋₆alkyl, wherein eachR^(a) is unsubstituted or substituted with one to six substituentsselected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl. In a classof this embodiment, each R^(a) is independently selected from the groupconsisting of: halogen, —C₁₋₆alkyl, and —O—C₁₋₆alkyl, wherein each alkylis unsubstituted or substituted with one to six substituents selectedfrom Cl, F, CF₃, OH, CH₃, and —OCH₃. In another class of thisembodiment, each R^(a) is independently selected from the groupconsisting of: Br, F, Cl, —CF₃, —CH₃, —CHF₂, —CH₂CF₃, —CF₂CH₃, —OCF₃,—OCHF₂, and —OCH₂CF₃. In another class of this embodiment, each R^(a) isindependently selected from the group consisting of: F, Cl, —CF₃, —CH₃,—CHF₂, —CH₂CF₃, —CF₂CH₃, —OCF₃, —OCHF₂, and —OCH₂CF₃. In another classof this embodiment, each R^(a) is independently selected from the groupconsisting of: F, Cl, —CF₃, —CH₃, —CHF₂, and —OCF₃.

In another embodiment, each R^(a) is independently selected from thegroup consisting of halogen, and —C₁₋₆alkyl, wherein each alkyl sunsubstituted or substituted with one to six substituents selected fromhalogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl. In a class of thisembodiment, each R^(a) is independently selected from the groupconsisting of: halogen, and —C₁₋₆alkyl, wherein each R^(a) isunsubstituted or substituted with one to six substituents selected fromCl, F, CF₃, OH, CH₃, and —OCH₃. In another class of this embodiment,each R^(a) is independently selected from the group consisting of: Br,F, Cl, —CF₃, —CH₃, —CHF₂, —CH₂CF₃, and —CF₂CH₃. In another class of thisembodiment, each R^(a) is independently selected from the groupconsisting of F, Cl, —CF₃, —CH₃, —CHF₂, —CH₂CF₃, and —CF₂CH₃. In anotherclass of this embodiment, each R^(a) is independently selected from thegroup consisting of: F, Cl, —CF₃, —CH₃, and —CHF₂.

In another embodiment, each R^(a) is halogen. In a class of thisembodiment, R^(a) is F or Cl. In another embodiment, R^(a) is—C₁₋₆alkyl, wherein each R^(a) is unsubstituted or substituted with oneto six substituents selected from F, Cl, CF₃, OH, CH₃, and —OCH₃. In aclass of this embodiment, R^(a) is —CF₃, —CH₃, or —CHF₂.

In one embodiment, each R^(b) is independently selected from the groupconsisting of: CN, oxo, halogen, —S(O)₂C₁₋₆alkyl, —C₁₋₆alkyl,—C₁₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl,aryl, heteroaryl, —C₁₋₆alkyl-aryl, —C₁₋₆alkyl-heteroaryl,—C₁₋₆alkyl-C₃₋₆cycloalkyl, —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl,—C₂₋₆alkenyl-C₃₋₆cycloalkyl, —C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl,—C₂₋₆alkenyl-aryl, —C₂₋₆alkenyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₆cycloalkyl,—C₂₋₆alkynyl-C₂₋₆cycloheteroalkyl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —OH, —(CH₂)_(q)—O—C₁₋₆alkyl,—(CH₂)_(q)—O—C₂₋₆alkenyl, —(CH₂)_(q) —O—C₂₋₆alkynyl, —(CH₂)_(q)—O—C₃₋₆cycloalkyl, —(CH₂)_(q) —O—C₂₋₆cycloheteroalkyl, —(CH₂)_(q)—O-aryl, —(CH₂)_(q) —O-heteroaryl, —OC₁₋₆alkyl-C₃₋₆cycloalkyl,—OC₁₋₆alkyl-C₂₋₆cycloheteroalkyl, —OC₁₋₆alkyl-aryl,—OC₁₋₆alkyl-heteroaryl, —S(O)_(r)R^(i), —C₁₋₆alkyl-S(O)_(r)R^(i),—N(R^(k))₂, —C(O)R^(L), and —NR^(k)R^(L), wherein each R^(b) isunsubstituted or substituted with one to six substituents selected fromhalogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and O—C₁₋₆alkyl.

In another embodiment, each R^(b) is independently selected from thegroup consisting of CN, oxo, halogen, —S(O)₂C₁₋₆alkyl, —C₁₋₆alkyl,—C₁₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl,aryl, heteroaryl, —C₁₋₆alkyl-aryl, —C₁₋₆alkyl-heteroaryl,—C₁₋₆alkyl-C₃₋₆cycloalkyl, —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl, —OH,—(CH₂)_(q)—O—C₁₋₆alkyl, —(CH₂)_(q)—O—C₂₋₆ alkenyl, —(CH₂)_(q)—O—C₂₋₆alkynyl, —(CH₂)_(q) —O—C₃₋₆cycloalkyl, —(CH₂)_(q)—O—C₂₋₆cycloheteroalkyl, —(CH₂)_(q) —O-aryl, —(CH₂)_(q) —O-heteroaryl,wherein each R^(b) is unsubstituted or substituted with one to sixsubstituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃,—C₁₋₆alkyl, and —OC₁₋₆alkyl.

In another embodiment, each R^(b) is independently selected from thegroup consisting of: CN, oxo, halogen, —S(O)₂C₁₋₆alkyl, —C₁₋₆alkyl,—C₁₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl,aryl, heteroaryl, —C₁₋₆alkyl-aryl, —C₁₋₆alkyl-heteroaryl,—C₁₋₆alkyl-C₃₋₆cycloalkyl, —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl, —OH,—O—C₁₋₆alkyl, —O—C₃₋₆cycloalkyl, and —O—C₂₋₆cycloheteroalkyl, whereineach R^(b) is unsubstituted or substituted with one to six substituentsselected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and—OC₁₋₆alkyl.

In another embodiment, each R^(b) is independently selected from thegroup consisting of: CN, oxo, halogen, —S(O)₂C₁₋₆alkyl, —C₁₋₆alkyl,—C₁₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl,aryl, heteroaryl, —OH, —O—C₁₋₆alkyl, —O—C₃₋₆cycloalkyl, and—O—C₂₋₆cycloheteroalkyl, wherein each R^(b) is unsubstituted orsubstituted with one to six substituents selected from halogen, CF₃,OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl.

In another embodiment, each R^(b) is independently selected from thegroup consisting of: CN, halogen, —C₁₋₆alkyl, —C₁₋₆alkenyl,—C₃₋₆cycloalkyl, —C₂₋₆cycloheteroalkyl, aryl, heteroaryl, —OH,—O—C₁₋₆alkyl, —O—C₃₋₆cycloalkyl, —O—C₂₋₆cycloheteroalkyl, wherein eachR^(b) is unsubstituted or substituted with one to six substituentsselected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and—OC₁₋₆alkyl.

In another embodiment, each R^(b) is independently selected from thegroup consisting of: CN, halogen, —C₁₋₆alkyl, —C₁₋₆alkenyl,—C₃₋₆cycloalkyl, aryl, heteroaryl, and —O—C₁₋₆alkyl, wherein each R^(b)is unsubstituted or substituted with one to six substituents selectedfrom halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, andO—C₁₋₆alkyl.

In another embodiment, each R^(b) is independently selected from thegroup consisting of: CN, halogen-C₁₋₆alkyl, —C₁₋₆alkenyl,—C₃₋₆cycloalkyl, and —OC₁₋₆alkyl, wherein alkyl, alkenyl and cycloalkylis unsubstituted or substituted with one to six substituents selectedfrom halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and—OC₁₋₆alkyl.

In another embodiment, each R^(b) is independently selected from thegroup consisting of: halogen, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₃₋₆cycloalkyl,and —O—C₁₋₆alkyl, wherein each R^(b) is unsubstituted or substitutedwith one to six substituents selected from halogen, CF₃, OCF₃, CN,CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl. In a class of thisembodiment, each R^(b) is independently selected from the groupconsisting of: halogen, —C₁₋₆alkyl, —C₁₋₆alkenyl, —C₃₋₆cycloalkyl, and—O—C₁₋₆alkyl, wherein each alkyl, alkenyl, and cycloalkyl isunsubstituted or substituted with one to six substituents selected fromF, Cl, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —CH₃, and —OCH₃. In another classof this embodiment, each R^(b) is independently selected from the groupconsisting of: F, Cl, —CH₃, —CF₃, —CH₂CF₃, —CH(CH₃)CF₃, —CF₂CH₃, ═CH₂,cyclopropyl, —OCH₃, —OCF₃, —OCHF₂, —OCH₂CF₃, wherein cyclopropyl isunsubstituted or substituted with one to five substituents selected fromF, Cl, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —CH₃, and O—CH₃. In another classof this embodiment, each R^(b) is independently selected from the groupconsisting of: F, Cl, —CH₃, —CF₃, —CH₂CF₃, —CH(CH₃)CF₃, =CH₂,cyclopropyl, —OCH₃, —OCHF₂, —OCH₂CF₃, wherein cyclopropyl isunsubstituted or substituted with one to five substituents selected fromF, Cl, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —CH₃, and P—CH₃.

In another embodiment, each R^(b) is independently selected from thegroup consisting of: halogen, and —C₁₋₆alkyl, wherein each R^(b) isunsubstituted or substituted with one to six substituents selected fromhalogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and O—C₁₋₆alkyl. Ina class of this embodiment, each R^(b) is independently selected fromthe group consisting of: halogen, and —C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with one to six substituents selected fromF, Cl, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —CH₃, and —OCH₃. In another classof this embodiment, each R^(b) is independently selected from the groupconsisting of: F, Cl, —CH₃, —CF₃, —CH₂CF₃, —CH(CH₃)CF₃, and —CF₂CH₃. Inanother class of this embodiment, each R^(b) is independently selectedfrom the group consisting of: F, Cl, —CH₃, —CF₃, —CH₂CF₃, and—CH(CH₃)CF₃.

In another embodiment, each R^(b) is halogen. In a class of thisembodiment, R^(b) is F or Cl. In another class of this embodiment, R^(b)is F. In another class of this embodiment, R^(b) is Cl.

In another embodiment, each R^(b) is —C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with one to six substituents selected fromF, Cl, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —CH₃, and —OCH₃. In a class ofthis embodiment, R^(b) is selected from: —CH₃, —CF₃, —CH₂CF₃,—CH(CH₃)CF₃, and —CF₂CH₃. In another class of this embodiment, R^(b) isselected from: —CH₃, —CF₃, —CH₂CF₃, and —CH(CH₃)CF₃. In another class ofthis embodiment, R^(b) is —CF₃.

In one embodiment, R^(c) is selected from: —C₁₋₆alkyl, OH, halogen, and—OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree halogens.

In another embodiment, R^(c) is selected from: —C₁₋₆alkyl, OH, andhalogen, wherein alkyl is unsubstituted or substituted with one to threehalogens. In another embodiment, R^(c) is selected from: C₁₋₆alkyl, andhalogen, wherein alkyl is unsubstituted or substituted with one to threehalogens. In a class of this embodiment, R^(c) is —C₁₋₆alkyl, whereinalkyl is unsubstituted or substituted with one to three halogens. Inanother class of this embodiment, R^(c) is halogen.

In one embodiment, R^(d) is selected from: —C₁₋₆alkyl, OH, halogen, and—OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree halogens. In another embodiment, R^(d) is selected from:—C₁₋₆alkyl, OH, and halogen, wherein alkyl is unsubstituted orsubstituted with one to three halogens. In another embodiment, R^(d) isselected from: —C₁₋₆alkyl and halogen, wherein alkyl is unsubstituted orsubstituted with one to three halogens. In a class of this embodiment,R^(d) is —C₁₋₆alkyl or F. In another embodiment, R^(d) is —C₁₋₆alkyl,wherein alkyl is unsubstituted or substituted with one to threehalogens. In another embodiment, R^(d) is halogen, wherein alkyl isunsubstituted or substituted with one to three halogens. In a class ofthis embodiment, R^(d) is F.

In one embodiment, R^(e) is selected from: hydrogen, and C₁₋₆alkyl. Inanother embodiment, R^(e) is hydrogen. In another embodiment, R^(e) isC₁₋₆alkyl.

In one embodiment, R^(f) is selected from: —C₁₋₆alkyl, OH, halogen, and—OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree halogens. In another embodiment, R^(f) is selected from:—C₁₋₆alkyl, OH, and halogen, wherein alkyl is unsubstituted orsubstituted with one to three halogens. In another embodiment, R^(f) isselected from: —C₁₋₆alkyl and halogen, wherein alkyl is unsubstituted orsubstituted with one to three halogens. In a class of this embodiment,R^(f) is —C₁₋₆alkyl or F. In another embodiment, R^(f) is —C₁₋₆alkyl,wherein alkyl is unsubstituted or substituted with one to threehalogens. In another embodiment, R^(f) is halogen, wherein alkyl isunsubstituted or substituted with one to three halogens. In a class ofthis embodiment, R^(f) is F.

In one embodiment, R^(g) is selected from: —C₁₋₆alkyl, OH, halogen, and—OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one tothree halogens. In another embodiment, R^(g) is selected from:—C₁₋₆alkyl, OH, and halogen, wherein alkyl is unsubstituted orsubstituted with one to three halogens. In another embodiment, R^(g) isselected from: —C₁₋₆alkyl and halogen, wherein alkyl is unsubstituted orsubstituted with one to three halogens. In a class of this embodiment,R^(g) is —C₁₋₆alkyl or F. In another embodiment, R^(g) is —C₁₋₆alkyl,wherein alkyl is unsubstituted or substituted with one to threehalogens. In another embodiment, R^(g) is halogen. In a class of thisembodiment, R^(g) is F.

In one embodiment, R^(h) is selected from: hydrogen, C₁₋₆alkyl,C₃₋₆cycloalkyl, aryl, and heteroaryl. In another embodiment, R^(h) isselected from: hydrogen, C₁₋₆alkyl, and C₃₋₆cycloalkyl. In anotherembodiment, R^(h) is selected from: hydrogen, and C₁₋₆alkyl. In anotherembodiment, R^(h) is hydrogen. In another embodiment, R^(h) isC₁₋₆alkyl.

In one embodiment, R^(i) is selected from: hydrogen, C₁₋₆alkyl,C₃₋₆cycloalkyl, aryl, and heteroaryl. In another embodiment, R^(i) isselected from: hydrogen, C₁₋₆alkyl, and C₃₋₆cycloalkyl. In anotherembodiment, R^(i) is selected from: hydrogen, and C₁₋₆alkyl. In anotherembodiment, R^(i) is hydrogen. In another embodiment, R^(i) isC₁₋₆alkyl.In one embodiment, R^(i) is selected from: hydrogen, C₁₋₆alkyl,C₃₋₆alkenyl, C₃₋₆alkynyl, C₃₋₆cycloalkyl, C₂₋₅cycloheteroalkyl, aryl,and heteroaryl. In another embodiment, R^(i) is selected from: hydrogen,C₁₋₆alkyl, C₃₋₆alkenyl, C₃₋₆alkynyl, C₃₋₆cycloalkyl, andC₂₋₅cycloheteroalkyl, In another embodiment, R^(j) is selected from:hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, and C₂₋₅cycloheteroalkyl. Inanother embodiment, R^(j) is selected from: hydrogen, and C₁₋₆alkyl. Inanother embodiment, R^(j) is hydrogen. In another embodiment, R^(j) isC₁₋₆alkyl.

In one embodiment, R^(k) is selected from: hydrogen, and C₁₋₆alkyl. Inanother embodiment, R^(k) is hydrogen. In another embodiment, R^(k) isC₁₋₆alkyl.

In one embodiment, R^(L) is selected from: hydrogen, C₁₋₆alkyl,C₃₋₆cycloalkyl, aryl, and heteroaryl. In another embodiment, R^(L) isselected from: hydrogen, C₁₋₆alkyl, and C₃₋₆cycloalkyl. In anotherembodiment, R^(L) is selected from: hydrogen, and C₁₋₆alkyl. In a classof this embodiment, R^(L) is hydrogen. In another class of thisembodiment, R^(L) is C₁₋₆alkyl. In one embodiment, m is 0, 1 or 2. Inanother embodiment, m is 0 or 1. In another embodiment, m is 0 or 2. Inanother embodiment, m is 0. In another embodiment, m is 1. In anotherembodiment, m is 2.

In one embodiment, n is 2, 3, 4, 5 or 6. In another embodiment, n is 2,3, 4, or 5. In another embodiment, n is 2, 3, or 4. In anotherembodiment, n is 2 or 3. In another embodiment, n is 2 or 4. In anotherembodiment, n is 2, 3, 4, or 5. In another embodiment, n is 3. Inanother embodiment, n is 4. In another embodiment, n is 5. In anotherembodiment, n is 6.

In one embodiment, p is 0, 1, 2 or 3. In another embodiment, p is 0, 1or 2. In another embodiment, p is 0, 1 or 3. In another embodiment, p is1, 2 or 3. In another embodiment, p is 1 or 2. In another embodiment, pis 1 or 3. In another embodiment, p is 0 or 1. In another embodiment, pis 0 or 2. In another embodiment, p is 0 or 3. In another embodiment, pis 0. In another embodiment, p is 1. In another embodiment, p is 2. Inanother embodiment, p is 3.

In one embodiment, q is 0, 1, 2 or 3. In another embodiment, q is 0, 1or 2. In another embodiment, q is 0, 1 or 3. In another embodiment, q is1, 2 or 3. In another embodiment, q is 1 or 2. In another embodiment, qis 1 or 3. In another embodiment, q is 0 or 1. In another embodiment, qis 0 or 2. In another embodiment, q is 0 or 3. In another embodiment, qis 0. In another embodiment, q is 1. In another embodiment, q is 2. Inanother embodiment, q is 3.

In one embodiment, r is 0, 1 or 2. In another embodiment, r is 0 or 1.In another embodiment, r is 0 or 2. In another embodiment, r is 0. Inanother embodiment, r is 1. In another embodiment, r is 2.

In one embodiment, s is 0, 1, 2, 3, 4, 5 or 6. In another embodiment, sis 0, 1, 2, 3, 4, or 5. In another embodiment, s is 1, 2, 3, 4, 5 or 6.In another embodiment, s is 1, 2, 3, 4 or 5. In another embodiment, s is0, 1, 2, 3, or 4. In another embodiment, s is 1, 2, 3, or 4. In anotherembodiment, s is 0, 1, 2, or 3. In another embodiment, s is 1, 2, or 3.In another embodiment, s is 0, 1 or 2. In another embodiment, s is 1 or2. In another embodiment, s is 0. In another embodiment, s is 1. Inanother embodiment, s is 2. In another embodiment, s is 3. In anotherembodiment, s is 4. In another embodiment, s is 5. In anotherembodiment, s is 6.

In one embodiment, t is 0, 1, 2, 3, 4, 5 or 6. In another embodiment, tis 0, 1, 2, 3, 4, or 5. In another embodiment, t is 1, 2, 3, 4, 5 or 6.In another embodiment, t is 1, 2, 3, 4 or 5. In another embodiment, t is0, 1, 2, 3, or 4. In another embodiment, t is 1, 2, 3, or 4. In anotherembodiment, t is 0, 1, 2, or 3. In another embodiment, t is 1, 2, or 3.In another embodiment, t is 0, 1 or 2. In another embodiment, t is 1 or2. In another embodiment, t is 0. In another embodiment, t is 1. Inanother embodiment, t is 2. In another embodiment, t is 3. In anotherembodiment, t is 4. In another embodiment, t is 5. In anotherembodiment, t is 6.

In another embodiment, provided are compounds of structural formula Ia:

or a pharmaceutically acceptable salt thereof.

In another embodiment, provided are compounds of structural formula Ib:

or a pharmaceutically acceptable salt thereof.

In a class of this embodiment, the pyridyl is:

In another class of this embodiment, the pyridyl is:

In another class of this embodiment, the pyridyl is:

In another embodiment, provided are compounds of structural formula Ic:

or a pharmaceutically acceptable salt thereof.

In another embodiment, provided are compounds of structural formula Id:

or a pharmaceutically acceptable salt thereof.

In another embodiment, provided are compounds of structural formula Ie:

or a pharmaceutically acceptable salt thereof.

In a class of this embodiment, the pyridyl is:

In another class of this embodiment, the pyridyl is:

In another class of this embodiment, the pyridyl is:

In another embodiment, provided are compounds of structural formula If:

or a pharmaceutically acceptable salt thereof.

The compound of structural formula I, includes the compounds ofstructural formulas Ia, Ib, 1c, Id, Ie and If, and pharmaceuticallyacceptable salts, hydrates and solvates thereof.

Another embodiment relates to compounds of structural formula I wherein:A is selected from the group consisting of:

-   -   (1) aryl, and    -   (2) heteroaryl,        wherein aryl and heteroaryl are unsubstituted or substituted        with one to five substituents selected from R^(a);        B is independently selected from the group consisting of:    -   (1) —C₃₋₁₂cycloalkyl,    -   (2) —C₂₋₁₁cycloheteroalkyl,    -   (3) —C₁₋₆alkyl-C₃₋₁₂cycloalkyl,    -   (4) —C₁₋₆alkyl-C₂₋₁₁cycloheteroalkyl,    -   (5) —C₁₋₆alkyl-O—C₃₋₁₂cycloalkyl, and    -   (6) —C₁₋₆alkyl-O—C₂₋₁₁cycloheteroalkyl,        wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted        or substituted with one to six substituents selected from R^(b);        and        R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(a), R^(b), R^(c), R^(d),        R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k), R^(L), m, n, p,        q, r, s and t are as defined above;        or a pharmaceutically acceptable salt thereof.

Another embodiment relates to compounds of structural formula I wherein:

A is selected from the group consisting of:

-   -   (1) phenyl,    -   (2) pyridine, and    -   (3) thiazole,        wherein phenyl, pyridine and thiazole are unsubstituted or        substituted with one to five substituents selected from R^(a);        B is independently selected from the group consisting of:    -   (1) cyclopropane,    -   (2) cyclobutane,    -   (3) cyclopentane,    -   (4) cyclohexane,    -   (5) bicyclo[3.2.1]octane,    -   (6) bicyclo[3.1.0]hexane,    -   (7) bicyclo[2.2.2]octane,    -   (8) spiro[2.5]octane,    -   (9) bicyclo[1.1.1]pentane,    -   (10) spiro[3.3]heptane,    -   (11) spiro[2.3]hexane, spiro[2.2]pentane    -   (12) piperidine,    -   (13) tetrahydropyran, and    -   (14) chromane,        wherein B is unsubstituted or substituted with one to six        substituents selected from R^(b).        R¹ is selected from the group consisting of:    -   (1) hydrogen, and    -   (2) —C₁₋₆alkyl, and        wherein each alkyl is unsubstituted or substituted with one to        five substituents selected from R^(c);        R² is selected from the group consisting of:    -   (1) hydrogen,    -   (2) deuterium,    -   (3) —C₁₋₆alkyl, and    -   (4) —C₃₋₆cycloalkyl,        wherein each alkyl and cycloalkyl is unsubstituted or        substituted with one to five substituents selected from R^(d);        R³ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) deuterium,    -   (3) —C₁₋₆alkyl, and    -   (4) —C₃₋₆cycloalkyl,        wherein each alkyl and cycloalkyl is unsubstituted or        substituted with one to five substituents selected from R^(d);        R⁴ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) deuterium,    -   (3) —C₁₋₆alkyl, and    -   (4) —C₃₋₆cycloalkyl,        wherein each alkyl and cycloalkyl is unsubstituted or        substituted with one to five substituents selected from R^(f);        R⁵ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) deuterium,    -   (3) —C₁₋₆alkyl, and    -   (4) —C₃₋₆cycloalkyl,        wherein alkyl and cycloalkyl is unsubstituted or substituted        with one to five substituents selected from R^(f);        R⁶ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, and    -   (3) —C₃₋₆cycloalkyl,        wherein alkyl and cycloalkyl is unsubstituted or substituted        with one to five substituents selected from R^(g);        R⁷ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, and    -   (3) —C₃₋₆cycloalkyl,        wherein alkyl, and cycloalkyl is unsubstituted or substituted        with one to five substituents selected from R^(g);        R⁸ is selected from the group consisting of:    -   (1) hydrogen, and    -   (2) —C₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to five        substituents selected from halogen;        R⁹ is selected from the group consisting of:    -   (1) hydrogen, and    -   (2) —C₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to five        substituents selected from halogen;        R^(a) is independently selected from the group consisting of:    -   (1) CN,    -   (2) oxo,    -   (3) halogen,    -   (4) —S(O)₂C₁₋₆alkyl,    -   (5) —C₁₋₆alkyl,    -   (6) —C₂₋₆alkenyl,    -   (7) —C₃₋₆cycloalkyl,    -   (8) —C₂₋₆cycloheteroalkyl,    -   (9) aryl,    -   (10) heteroaryl,    -   (11) —OH,    -   (12) —O—C₁₋₆alkyl,    -   (13) —O—C₃₋₆cycloalkyl, and    -   (14) —O—C₂₋₆cycloheteroalkyl,        wherein each R^(a) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and        —OC₁₋₆alkyl; and        each R^(b) is independently selected from the group consisting        of:    -   (1) CN,    -   (2) oxo,    -   (3) halogen,    -   (4) —S(O)₂C₁₋₆alkyl,    -   (5) —C₁₋₆alkyl,    -   (6) —C₁₋₆alkenyl,    -   (7) —C₂₋₆alkynyl,    -   (8) —C₃₋₆cycloalkyl,    -   (9) —C₂₋₆cycloheteroalkyl,    -   (10) aryl,    -   (11) heteroaryl,    -   (12) —OH,    -   (13) —O—C₁₋₆alkyl,    -   (14) —O—C₃₋₆cycloalkyl, and    -   (15) —O—C₂₋₆cycloheteroalkyl,        wherein each R^(b) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃,        CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; and        R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k),        R^(L), m, n, p, q, r, s and t are as defined above;        or a pharmaceutically acceptable salt thereof.

Another embodiment relates to compounds of structural formula I wherein:

A is selected from the group consisting of:

-   -   (1) phenyl,    -   (2) pyridine, and    -   (3) thiazole,        wherein phenyl, pyridine and thiazole are unsubstituted or        substituted with one to five substituents selected from R^(a);        B is independently selected from the group consisting of:    -   (1) cyclopropane,    -   (2) cyclobutane,    -   (3) cyclopentane,    -   (4) cyclohexane,    -   (5) bicyclo[3.2.1]octane,    -   (6) bicyclo[3.1.0]hexane,    -   (7) bicyclo[2.2.2]octane,    -   (8) spiro[2.5]octane,    -   (9) bicyclo[1.1.1]pentane,    -   (10) spiro[3.3]heptane,    -   (11) spiro[2.3]hexane,    -   (12) spiro[2.2]pentane    -   (13) piperidine, and    -   (14) tetrahydropyran,        wherein B is unsubstituted or substituted with one to six        substituents selected from R^(b).        R¹ is selected from the group consisting of:    -   (1) hydrogen, and    -   (2) —C₁₋₆alkyl, and        wherein each alkyl is unsubstituted or substituted with one to        five substituents selected from R^(c);        R² is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, and    -   (3) —C₃₋₆cycloalkyl,        wherein each alkyl and cycloalkyl is unsubstituted or        substituted with one to five substituents selected from R^(d);        R³ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, and    -   (3) —C₃₋₆cycloalkyl,        wherein each alkyl and cycloalkyl is unsubstituted or        substituted with one to five substituents selected from R^(d);        R⁴ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, and    -   (3) —C₃₋₆cycloalkyl,        wherein each alkyl and cycloalkyl is unsubstituted or        substituted with one to five substituents selected from R^(f);        R⁵ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, and    -   (3) —C₃₋₆cycloalkyl,        wherein alkyl and cycloalkyl is unsubstituted or substituted        with one to five substituents selected from R^(f);        R⁶ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, and    -   (3) —C₃₋₆cycloalkyl,        wherein alkyl and cycloalkyl is unsubstituted or substituted        with one to five substituents selected from R^(g);        R⁷ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, and    -   (3) —C₃₋₆cycloalkyl,        wherein alkyl, and cycloalkyl is unsubstituted or substituted        with one to five substituents selected from R^(g);        R⁸ is selected from the group consisting of:    -   (1) hydrogen, and    -   (2) —C₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to five        substituents selected from halogen;        R⁹ is selected from the group consisting of:    -   (1) hydrogen, and    -   (2) —C₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with one to five        substituents selected from halogen;        R^(a) is independently selected from the group consisting of:    -   (1) CN,    -   (2) oxo,    -   (3) halogen,    -   (4) —S(O)₂C₁₋₆alkyl,    -   (5) —C₁₋₆alkyl,    -   (6) —C₂₋₆alkenyl,    -   (7) —C₃₋₆cycloalkyl,    -   (8) —C₂₋₆cycloheteroalkyl,    -   (9) aryl,    -   (10) heteroaryl,    -   (11) —OH,    -   (12) —O—C₁₋₆alkyl,    -   (13) —O—C₃₋₆cycloalkyl, and    -   (14) —O—C₂₋₆cycloheteroalkyl,        wherein each R^(a) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and        —OC₁₋₆alkyl;        each R^(b) is independently selected from the group consisting        of:    -   (1) CN,    -   (2) oxo,    -   (3) halogen,    -   (4) —S(O)₂C₁₋₆alkyl,    -   (5) —C₁₋₆alkyl,    -   (6) —C₁₋₆alkenyl,    -   (7) —C₂₋₆alkynyl,    -   (8) —C₃₋₆cycloalkyl,    -   (9) —C₂₋₆cycloheteroalkyl,    -   (10) aryl,    -   (11) heteroaryl,    -   (12) —OH,    -   (13) —O—C₁₋₆alkyl,    -   (14) —O—C₃₋₆cycloalkyl, and    -   (15) —O—C₂₋₆cycloheteroalkyl,        wherein each R^(b) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃,        CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; and        R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k),        R^(L), m, n, p, q, r, s and t are as defined above; or a        pharmaceutically acceptable salt thereof.

Another embodiment relates to compounds of structural formula I wherein:

A is selected from the group consisting of:

-   -   (1) phenyl, and    -   (2) pyridine,        wherein phenyl and pyridine are unsubstituted or substituted        with one to four substituents selected from R^(a);        B is independently selected from the group consisting of:    -   (1) —C₃₋₁₂cycloalkyl, and    -   (2) —C₂₋₁₁cycloheteroalkyl,        wherein cycloalkyl and cycloheteroalkyl are unsubstituted or        substituted with one to six substituents selected from R^(b);        R¹ is hydrogen;        R², R³, R⁴ and R⁵ are deuterium or hydrogen;        R⁶ and R⁷ are CH₃ or hydrogen;        R⁸ and R⁹ are hydrogen;        each R^(a) is independently selected from the group consisting        of:    -   (1) halogen,    -   (2) —C₁₋₆alkyl, and    -   (3) —O—C₁₋₆alkyl,        wherein each R^(a) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and        —OC₁₋₆alkyl;        each R^(b) is independently selected from the group consisting        of:    -   (1) halogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₁₋₆alkenyl,    -   (4) —C₃₋₆cycloalkyl, and    -   (5) —O—C₁₋₆alkyl,        wherein each R^(b) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃,        CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; and        R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k),        R^(L), m, n, p, q, r, s and t are as defined above;        or a pharmaceutically acceptable salt thereof.

Another embodiment relates to compounds of structural formula I wherein:

A is selected from the group consisting of:

-   -   (1) phenyl, and    -   (2) pyridine,        wherein phenyl and pyridine are unsubstituted or substituted        with one to four substituents selected from R^(a);        B is independently selected from the group consisting of:    -   (1) —C₃₋₁₂cycloalkyl, and    -   (2) —C₂₋₁₁cycloheteroalkyl,        wherein cycloalkyl and cycloheteroalkyl are unsubstituted or        substituted with one to six substituents selected from R^(b);        R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are hydrogen;        each R^(a) is independently selected from the group consisting        of    -   (1) halogen,    -   (2) —C₁₋₆alkyl, and    -   (3) —O—C₁₋₆alkyl,        wherein each R^(a) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and        —OC₁₋₆alkyl;        each R^(b) is independently selected from the group consisting        of    -   (1) halogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₁₋₆alkenyl,    -   (4) —C₃₋₆cycloalkyl, and    -   (5) —O—C₁₋₆alkyl,        wherein each R^(b) is unsubstituted or substituted with one to        six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃,        CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; and        R^(c), R^(d), R^(e), R^(f), R^(g), R^(h), R^(i), R^(j), R^(k),        R^(L), m, n, p, q, r, s and t are as defined above;        or a pharmaceutically acceptable salt thereof.

Illustrative, but non-limiting, examples of the compounds that areuseful as inhibitors of Na_(v)1.8 channel activity are the followingcompounds:

-   (1)    N—((R)-3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (2)    N—((S)-3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (3)    N—((R)-(3-chloro-4-fluorophenyl)(8,8-difluorobicyclo[3.2.1]octan-3-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (4)    N—((S)-(3-chloro-4-fluorophenyl)(8,8-difluorobicyclo[3.2.1]octan-3-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (5)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(8,8-difluorobicyclo[3.2.1]octan-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (6)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(8,8-difluorobicyclo[3.2.1]octan-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (7)    N—((R)-(4-chlorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (8)    N—((R)-(4-chlorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (9)    N—((S)-(4-chlorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (10)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (11)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (12)    (R)-2-methyl-3-oxo-N—((R)-(trans-4-(trifluoromethyl)cyclohexyl)(3,4,5-trifluorophenyl)methyl)piperazine-1-carboxamide;-   (13)    (R)-2-methyl-3-oxo-N—((S)-(trans-4-(trifluoromethyl)cyclohexyl)(3,4,5-trifluorophenyl)methyl)piperazine-1-carboxamide;-   (14)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (15)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (16)    (2R)—N—((R)-(3,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (17)    (2R)—N—((S)-(3,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (18)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (19)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (20)    N—((R)-(3-chloro-2,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (21)    N—((S)-(3-chloro-2,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (22)    (R)—N—((R)-(3-chloro-2,4-difluorophenyl)((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (23)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((1R,3s,5S)-6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (24)    N—((R)-(3-chloro-4-fluorophenyl)(4-(trifluoromethyl)bicyclo[2.2.2]octan-1-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (25)    N—((S)-(3-chloro-4-fluorophenyl)(4-(trifluoromethyl)bicyclo[2.2.2]octan-1-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (26)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(4,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (27)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(4,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (28)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(4,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (29)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(4,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (30)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (31)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (32)    (2R)—N—((R)-(4-chlorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (33)    (2R)—N—((S)-(4-chlorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (34)    N—((R)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (35)    N—((S)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (36)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(1-(R)-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (37)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(1-(S)-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (38)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(1-(R)-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (39)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(1-(S)-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (40)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(trans-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (41)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(trans-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (42)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(cis-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (43)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(cis-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (44)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (45)    (R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (46)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (47)    (R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (48)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-cyclopropylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (49)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-cyclopropylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (50)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-cyclopropylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (51)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-cyclopropylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (52)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-1,1-difluorospiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (53)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-1,1-difluorospiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (54)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-1,1-difluorospiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (55)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-1,1-difluorospiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (56)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(6,6-difluorospiro[3.3]heptan-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (57)    2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(6,6-difluorospiro[3.3]heptan-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (58)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(3,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (59)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(3,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (60)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(3-methylenecyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (61)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(3-methylenecyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (62)    N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-3-oxopiperazine-1-carboxamide;-   (63)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-cyclopropyl-3-oxopiperazine-1-carboxamide;-   (64)    (S)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-cyclopropyl-3-oxopiperazine-1-carboxamide;-   (65)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(spiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (66)    (2R)—N—((S)(3-chloro-2,4-difluorophenyl)(spiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (67)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (68)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (69)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (70)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (71)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(3,3-dimethylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (72)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(3,3-dimethylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (73)    N—((R)-(3-chloro-2,4-difluorophenyl)(3,3-dimethylcyclobutyl)methyl)-3-oxopiperazine-1-carboxamide;-   (74)    N—((S)-(3-chloro-2,4-difluorophenyl)(3,3-dimethylcyclobutyl)methyl)-3-oxopiperazine-1-carboxamide;-   (75)    (2R)—N—((R)-(3,3-dimethylcyclobutyl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (76)    (2R)—N—((S)-(3,3-dimethylcyclobutyl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (77)    N—((R)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (78)    N—((S)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-3-oxopiperazine-1-carboxamide;-   (79)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (80)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (81)    (2R)—N—((R)-(4-fluoro-3-methylphenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (82)    (2R)—N—((S)-(4-fluoro-3-methylphenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (83)    (2R)—N—((R)-(4-fluoro-3-methylphenyl)(cis-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (84)    (2R)—N—((S)-(4-fluoro-3-methylphenyl)(cis-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (85)    (2R)—N—((R)-(4-chloro-3-(difluoromethyl)phenyl)(cis-4-(trifluoromethyl)    cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (86)    (2R)—N—((R)-(4-chloro-3-(difluoromethyl)phenyl)(trans-4-(trifluoromethyl)    cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (87)    (2R)—N—((S)-(4-chloro-3-(difluoromethyl)phenyl)(cis-4-(trifluoromethyl)    cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (88)    (2R)—N—((S)-(4-chloro-3-(difluoromethyl)phenyl)(trans-4-(trifluoromethyl)    cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (89)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(trans-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (90) (2R)—N—((R)-(3-chloro-4-fluorophenyl) (cis-3-(difluoromethoxy)    cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (91) (2R)—N—((S)-(3-chloro-4-fluorophenyl) (cis-3-(difluoromethoxy)    cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (92)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(trans-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (93)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (94)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (95)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (96)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (97)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (98)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (99)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (100)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (101)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((R)-spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (102)    (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((S)-spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (103)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(R)-spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (104)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((S)-spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (105) (2R)—N—((R)-(3-chloro-2,4-difluoro    phenyl)((R)-3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (106) (2R)—N—((R)-(3-chloro-2,4-difluoro    phenyl)((S)-3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (107)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((R)-(3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (108)    (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((S)-3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (109)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (110)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (111)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (112)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (113)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(cis-3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (114)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(cis-3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (115)    (2R)—N—((R)-(3-chloro-4-fluorophenyl)(trans-3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (116)    (2R)—N—((S)-(3-chloro-4-fluorophenyl)(trans-3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (117)    N—((R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-4-(trifluoromethyl)cyclohexyl)-   methyl)-3-oxopiperazine-1-carboxamide;-   (118)    N—((S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-4-(trifluoromethyl)cyclo-hexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (119)    (2R)—N—((R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(4,4-difluorocyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (120)    (2R)—N—((S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(4,4-difluorocyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (121) (2R)—N—((R or    S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (122) (2R)—N—((R or    S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (123) (2R)—N—((S or    R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (124) (2R)—N—((S or    R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (125) (2R)—N—((R or    S)-1-(3-chloro-4-fluorophenyl)-1-(cis-3-(trifluoromethyl)cyclobutyl)-   ethyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (126) (2R)—N—((R or    S)-1-(3-chloro-4-fluorophenyl)-1-(trans-3-(trifluoromethyl)cyclobutyl)-ethyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (127) (2R)—N—((S or    R)-1-(3-chloro-4-fluorophenyl)-1-(cis-3-(trifluoromethyl)cyclobutyl)-ethyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (128) (2R)—N—((S or    R)-1-(3-chloro-4-fluorophenyl)-1-(trans-3-(trifluoromethyl)cyclobutyl)-ethyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (129)    (2R)—N—((R)-(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclo-butyl)-   methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (130)    (2R)—N—((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclo-butyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (131)    ((2R)—N—((R)-(2-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclo-butyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (132)    (2R)—N—((S)-(2-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclo-butyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (133)    (2R)—N—((R)-(4-fluoro-3-(trifluoromethyl)phenyl)(trans-3-(trifluoromethyl)cyclo-butyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (134)    (2R)—N—((S)-(4-fluoro-3-(trifluoromethyl)phenyl)(trans-3-(trifluoromethyl)-cyclo-butyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (135) N—((R)-(4-fluoro-3-(trifluoromethyl)phenyl)(trans-3-(trifluoro    methyl)cyclobutyl)-methyl)-3-oxopiperazine-1-carboxamide;-   (136) N—((S)-(4-fluoro-3-(trifluoromethyl)phenyl)(trans-3-(trifluoro    methyl)cyclobutyl)-methyl)-3-oxopiperazine-1-carboxamide;-   (137)    (2R)—N—((R)-(3-chloro-2-fluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (138)    (2R)—N—((S)-(3-chloro-2-fluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (139)    (2R)—N—((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)    cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (140)    (2R)—N—((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl)    cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (141)    (2R)-2-methyl-3-oxo-N-((trans-4-(trifluoromethyl)cyclohexyl)((R)-2-(trifluoro-methyl)thiazol-4-yl)methyl)piperazine-1-carboxamide;-   (142) (2R)-2-methyl-3-oxo-N-((trans-4-(trifluoromethyl)    cyclohexyl)((S)-2-(trifluoro-methyl)thiazol-4-yl)methyl)piperazine-1-carboxamide;-   (143) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((3R,    6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (144) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((3S,    6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (145) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((3R,    6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (146) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((3S,    6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (147)    (2R)—N—(R)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (148)    (2R)—N—(R)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (149)    (2R)—N—(S)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (150)    (2R)—N—(S)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (151) (2R)—N—((R or    S)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (152) (2R)—N—((R or    S)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (153) (2R)—N—((R or    S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;    and-   (154) (2R)—N—((R or    S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide;    or a pharmaceutically acceptable salt thereof.

Illustrative, but non-limiting, examples of the compounds that areuseful as inhibitors of Na_(v)1.8 channel activity are the followingcompounds:

-   (1)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-5,5,6,6-d4-1-carboxamide;-   (2)    (S)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-5,5,6,6-d4-1-carboxamide;-   (3) (2R)—N-((1(R or    S))-(4-fluoro-3-(trifluoromethyl)phenyl)-trans-(6-(trifluoromethyl)-tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (4) (2R)—N-((1(R or    S))-(4-fluoro-3-(trifluoromethyl)phenyl)-trans-(6-(trifluoromethyl)-tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (5)    (S)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-(fluoromethyl)-3-oxopiperazine-2-d-1-carboxamide;-   (6)    (R)—N—((R)-(3-chloro-2,4-difluorophenyl)((R)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;    s-   (7)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((R)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (8)    (R)—N—((R)-(3-chloro-2,4-difluorophenyl)((S)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (9)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((S)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (10)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxo-2-(trifluoromethyl)piperazine-1-carboxamide;-   (11)    (S)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxo-2-(trifluoromethyl)piperazine-1-carboxamide;    and-   (12)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-(hydroxymethyl)-3-oxopiperazine-1-carboxamide;    or a pharmaceutically acceptable salt thereof.

Illustrative, but non-limiting, examples of the compounds that areuseful as inhibitors of Na_(v)1.8 channel activity are the followingcompounds:

-   (1)    N—((R)-3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (2)    N—((S)-3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (3)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (4)    (R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (5)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (6)    (R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (7)    N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-3-oxopiperazine-1-carboxamide;-   (8) (2R)—N—((R or    S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (9) (2R)—N—((R or    S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (10) (2R)—N—((S or    R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (11) (2R)—N—((S or    R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (12) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((3R,    6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (13) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((3S,    6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (14) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((3R,    6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;    and-   (15) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((3S,    6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;    or a pharmaceutically acceptable salt thereof.

Illustrative, but non-limiting, examples of the compounds that areuseful as inhibitors of Na_(v)1.8 channel activity are the followingcompounds:

-   (1)    N—((R)-3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (2)    N—((S)-3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide;-   (3)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (4)    (R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (5)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (6)    (R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (7)    N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-3-oxopiperazine-1-carboxamide;-   (8) (2R)—N—((R or    S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (9) (2R)—N—((R or    S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (10) (2R)—N—((S or    R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (11) (2R)—N—((S or    R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (12) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((3R,    6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (13) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((3S,    6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (14) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((3R,    6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;    and-   (15) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((3S,    6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide;-   (16)    (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-5,5,6,6-d4-1-carboxamide;    and-   (17)    (S)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-5,5,6,6-d4-1-carboxamide;    or a pharmaceutically acceptable salt thereof.

Although the specific stereochemistries described above are preferred,other stereoisomers, including diastereoisomers, enantiomers, epimers,and mixtures of these may also have utility in treating Na_(v)1.8mediated diseases.

Synthetic methods for making the compounds are disclosed in the Examplesshown below. Where synthetic details are not provided in the examples,the compounds are readily made by a person of ordinary skill in the artof medicinal chemistry or synthetic organic chemistry by applying thesynthetic information provided herein. Where a stereochemical center isnot defined, the structure represents a mixture of stereoisomers at thatcenter. For such compounds, the individual stereoisomers, includingenantiomers, diastereoisomers, and mixtures of these are also compoundsof structural formula I.

Definitions

“Ac” is acetyl, which is CH₃C(═O)—.

“Alkyl” means saturated carbon chains which may be linear or branched orcombinations thereof, unless the carbon chain is defined otherwise.Other groups having the prefix “alk”, such as alkoxy and alkanoyl, alsomay be linear or branched, or combinations thereof, unless the carbonchain is defined otherwise. Examples of alkyl groups include methyl,ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl,heptyl, octyl, nonyl, and the like.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched, or combinationsthereof, unless otherwise defined. Examples of alkenyl include vinyl,allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like. In certain embodiments, alkenyl is—C₁alkenyl or ═CH₂.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched, or combinationsthereof, unless otherwise defined. Examples of alkynyl include ethynyl,propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means a saturated monocyclic, bicyclic, spirocyclic orbridged carbocyclic ring, having a specified number of carbon atoms. Thecycloalkyl ring may be fused to a phenyl ring. C₃₋₁₂cycloalkyl means asaturated monocyclic, bicyclic, spirocyclic or bridged carbocyclic ring,with three to twelve carbon atoms. The C₃₋₁₂cycloalkyl may be fused to aphenyl ring. C₃₋₁₀cycloalkyl means a saturated monocyclic, bicyclic,spirocyclic or bridged carbocyclic ring, with three to ten carbon atoms.The C₃₋₁₀cycloalkyl may be fused to a phenyl ring. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and the like. In one embodiment, cycloalkyl is cyclopropyl.In another embodiment, cycloalkyl is selected from: cyclopropane,cyclobutane, cyclopentane, and cyclohexane. In another embodiment,cycloalkyl is selected from: cyclopropane, cyclobutane, cyclopentane,cyclohexane, bicyclo[3.2.1]octane, bicyclo[3.1.0]-hexane,bicyclo[2.2.2]octane, spiro[2.5]octane, bicyclo[1.1.1]pentane,spiro[3.3]heptane, spiro[2.3]hexane, and spiro[2.2]pentane. In anotherembodiment, cycloalkyl is selected from: cyclobutane, and cyclohexane.In another embodiment, cycloalkyl is cyclopropane.

“Cycloheteroalkyl” means a saturated or partly unsaturated non-aromaticmonocyclic, bicyclic, spirocyclic or bridged ring or ring system havinga specified number of carbon atoms and containing at least one ringheteroatom selected from N, NH, S (including SO and SO₂) and O. Thecycloheteroalkyl ring may be fused to a phenyl ring. Thecycloheteroalkyl ring may be substituted on the ring carbons and/or thering nitrogen or sulfur. C₂₋₁₁cycloheteroalkyl means a saturated orpartly unsaturated non-aromatic monocyclic, bicyclic, spirocyclic orbridged ring or ring system with two to eleven carbon atoms andcontaining at least one ring heteroatom selected from N, NH, S(including SO and SO₂) and O. The cycloheteroalkyl ring may besubstituted on the ring carbons and/or the ring nitrogen or sulfur. TheC₂₋₁₁cycloheteroalkyl may be fused to a phenyl ring. C ₂₋₉cycloheteroalkyl means a saturated or partly unsaturated non-aromaticmonocyclic, bicyclic, spirocyclic or bridged ring or ring system withtwo to nine carbon atoms and containing at least one ring heteroatomselected from N, NH, S (including SO and SO₂) and O. Thecycloheteroalkyl ring may be substituted on the ring carbons and/or thering nitrogen or sulfur. The C ₂₋₉ cycloheteroalkyl may be fused to aphenyl ring. Examples of cycloheteroalkyl include tetrahydrofuran,pyrrolidine, tetrahydrothiophene, azetidine, piperazine, piperidine,morpholine, oxetane and tetrahydropyran. In one embodiment,cycloheteroalkyl is selected from: azetidine, piperidine, pyrrolidine,tetrahydropyran, and tetrahydrofuran. In another embodiment,cycloheteroalkyl is selected from: piperidine, and tetrahydropyran. Inanother embodiment, cycloheteroalkyl is tetrahydropyran. In anotherembodiment, cycloheteroalkyl is chromane.

“Aryl” means a monocyclic, bicyclic or tricyclic carbocyclic aromaticring or ring system containing 6-14 carbon atoms, wherein at least oneof the rings is aromatic. Examples of aryl include phenyl and naphthyl.In one embodiment, aryl is phenyl. In another embodiment, aryl isselected from phenyl and naphthalene.

“Heteroaryl” means a monocyclic, bicyclic or tricyclic ring or ringsystem containing 5-14 ring atoms and containing at least one ringheteroatom selected from N, NH, S (including SO and SO₂) and O, whereinat least one of the heteroatom containing rings is aromatic. Examples ofheteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl,pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl,triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl,pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl,isoquinolyl, quinazolinyl, dibenzofuranyl, and the like. In oneembodiment, heteroaryl is selected from pyridine and thiazole. Inanother embodiment, heteroaryl is pyridine. In another embodiment,heteroaryl is thiazole. In another embodiment, heteroaryl is selectedfrom: pyridine, pyrimidine, pyrazine, pyridazine, imidazole, pyrazole,thiazole, oxazole, benzofuran, benzoxazole, benzothiazole, indole,indazole, imidazopyridine, thiophene, and thiazolopyridine. In anotherembodiment, heteroaryl is pyridine.

“Halogen” includes fluorine, chlorine, bromine and iodine. In oneembodiment, halogen is fluorine, chorine or bromine. In anotherembodiment, halogen is fluorine or chlorine. In another embodiment,halogen is fluorine or bromine. In another embodiment, halogen isfluorine. In another embodiment, halogen is chlorine. In anotherembodiment, halogen is bromine.

“Me” represents methyl.

“Oxo” represents=O.

“Saturated” means containing only single bonds.

“Unsaturated” means containing at least one double or triple bond. Inone embodiment, unsaturated means containing at least one double bond.In another embodiment, unsaturated means containing one double bond. Inanother embodiment, unsaturated means containing at least one triplebond. In another embodiment, unsaturated means containing one triplebond.

When any variable (e.g., R¹, R^(a), etc.) occurs more than one time inany constituent or in structural formula I, its definition on eachoccurrence is independent of its definition at every other occurrence.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds. A squiggly line acrossa bond in a substituent variable represents the point of attachment.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to:

In choosing compounds, one of ordinary skill in the art will recognizethat the various substituents, i.e. R¹, R², etc., are to be chosen inconformity with well-known principles of chemical structure connectivityand stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, salts and/or dosage formswhich are, using sound medical judgment, and following all applicablegovernment regulations, safe and suitable for administration to a humanbeing or an animal.

Compounds of structural formula I may contain one or more asymmetriccenters and can thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Thepresent disclosure is meant to encompass all such isomeric forms of thecompounds of structural formula I.

The independent syntheses of optical isomers and diastereoisomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the X-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration or sufficient heavy atoms to makean absolute assignment.

If desired, racemic mixtures of the compounds may be separated so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well-known in the art, such as the coupling of a racemicmixture of compounds to an enantiomerically pure compound to form adiastereoisomeric mixture, followed by separation of the individualdiastereoisomers by standard methods, such as fractional crystallizationor chromatography. The coupling reaction is often the formation of saltsusing an enantiomerically pure acid or base. The diasteromericderivatives may then be converted to the pure enantiomers by cleavage ofthe added chiral residue. The racemic mixture of the compounds can alsobe separated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.

Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers as well asmixture thereof are encompassed with compounds of structural formula I.

In the compounds of general structural formula I, the atoms may exhibittheir natural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominately found in nature. The present disclosure ismeant to include all suitable isotopic variations of the compounds ofstructural formula I. For example, different isotopic forms of hydrogen(H) include protium (¹H), deuterium (²H), and tritium (³H). Protium isthe predominant hydrogen isotope found in nature. Enriching fordeuterium may afford certain therapeutic advantages, such as increasingin vivo half-life or reducing dosage requirements, or may provide acompound useful as a standard for characterization of biologicalsamples. Tritium is radioactive and may therefore provide for aradiolabeled compound, useful as a tracer in metabolic or kineticstudies. Isotopically-enriched compounds within structural formula I,can be prepared without undue experimentation by conventional techniqueswell known to those skilled in the art or by processes analogous tothose described in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

Furthermore, some of the crystalline forms for compounds may exist aspolymorphs and as such are intended to be included in the presentdisclosure. In addition, some of the compounds of structural formula Imay form solvates with water or common organic solvents. Such solvatesare encompassed within the scope of this disclosure.

It is generally preferable to administer compounds as enantiomericallypure formulations. Racemic mixtures can be separated into theirindividual enantiomers by any of a number of conventional methods. Theseinclude chiral chromatography, derivatization with a chiral auxiliaryfollowed by separation by chromatography or crystallization, andfractional crystallization of diastereomeric salts.

Salts

It will be understood that, as used herein, references to the compoundsare meant to also include the pharmaceutically acceptable salts, andalso salts that are not pharmaceutically acceptable when they are usedas precursors to the free compounds or their pharmaceutically acceptablesalts or in other synthetic manipulations.

The compounds may be administered in the form of a pharmaceuticallyacceptable salt. The term “pharmaceutically acceptable salt” refers tosalts prepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic or organic bases and inorganic or organic acids.Salts of basic compounds encompassed within the term “pharmaceuticallyacceptable salt” refer to non-toxic salts of the compounds of thisdisclosure which are generally prepared by reacting the free base with asuitable organic or inorganic acid. Representative salts of basiccompounds include, but are not limited to, the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate,pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide, trifluoroacetateand valerate. Furthermore, where the compounds of structural formula Icarry an acidic moiety, suitable pharmaceutically acceptable saltsthereof include, but are not limited to, salts derived from inorganicbases including aluminum, ammonium, calcium, copper, ferric, ferrous,lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, andthe like. Particularly preferred are the ammonium, calcium, magnesium,potassium, and sodium salts. Salts derived from pharmaceuticallyacceptable organic non-toxic bases include salts of primary, secondary,and tertiary amines, cyclic amines, and basic ion-exchange resins, suchas arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

Also, in the case of a carboxylic acid (—COOH) or alcohol group beingpresent in the compounds, pharmaceutically acceptable esters ofcarboxylic acid derivatives, such as methyl, ethyl, orpivaloyloxymethyl, or acyl derivatives of alcohols, such as O-acetyl,O-pivaloyl, O-benzoyl, and O-aminoacyl, can be employed. Included arethose esters and acyl groups known in the art for modifying thesolubility or hydrolysis characteristics for use as sustained-release orprodrug formulations.

The term “prodrug” means compounds that are rapidly transformed, forexample, by hydrolysis in blood, in vivo to the parent compound, e.g.,conversion of a prodrug of structural formula I to a compound ofstructural formula I, or to a salt thereof; a thorough discussion isprovided in T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche,ed., Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference. This disclosure includes prodrugs of the novelcompounds of structural formula I.

Solvates, and in particular, the hydrates of the compounds are includedin the present disclosure as well.

Utilities

The compound are selective inhibitors of Na_(v)1.8 sodium ion channelactivity or have selective activity as Na_(v)1.8 sodium ion channelblockers. In one embodiment, the compounds exhibit at least 10-foldselectivity for Na_(v)1.8 sodium channels over Na_(v)1.5 sodiumchannels, and in some embodiments exhibit at least 100-fold selectivityfor Na_(v)1.8 sodium channels over Na_(v)1.5 sodium channels based onfunctional potency (IC₅₀ values) for each channel in Qube® assay system.

The compounds are potent inhibitors of Na_(v)1.8 channel activity. Thecompounds, and pharmaceutically acceptable salts thereof, may beefficacious in the treatment of diseases, disorders and conditions thatare mediated by the inhibition of Na_(v)1.8 sodium ion channel activityand/or Na_(v)1.8 receptors.

Diseases, disorders or conditions mediated by Na_(v)1.8 sodium ionchannel activity and/or Na_(v)1.8 receptors, include but are not limitedto nociception, osteoarthritis, peripheral neuropathy, inheritederythromelalgia, multiple sclerosis, asthma, pruritus, acute itch,chronic itch, migraine, neurodegeneration following ischemia, epilepsy,inflammatory pain, spontaneous pain, acute pain, peri-operative pain,post-operative pain, neuropathic pain, postherpetic neuralgia,trigeminal neuralgia, diabetic neuropathy, chronic lower back pain,phantom limb pain, pain resulting from cancer and chemotherapy, chronicpelvic pain, pain syndromes, and complex regional pain syndromes.

One or more of these conditions or diseases may be treated, managed,prevented, reduced, alleviated, ameliorated or controlled by theadministration of a therapeutically effective amount of a compound, or apharmaceutically acceptable salt thereof, to a patient in need oftreatment. Also, the compounds may be used for the manufacture of amedicament which may be useful for treating, preventing, managing,alleviating, ameliorating or controlling one or more of theseconditions, diseases or disorders: nociception, osteoarthritis,peripheral neuropathy, inherited erythromelalgia, multiple sclerosis,asthma, pruritus, acute itch, chronic itch, migraine, neurodegenerationfollowing ischemia, epilepsy, inflammatory pain, spontaneous pain, acutepain, pen-operative pain, post-operative pain, neuropathic pain,postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy,chronic lower back pain, phantom limb pain, pain resulting from cancerand chemotherapy, chronic pelvic pain, pain syndromes, and complexregional pain syndromes.

Preferred uses of the compounds may be for the treatment of one or moreof the following diseases by administering a therapeutically effectiveamount to a patient in need of treatment. The compounds may be used formanufacturing a medicament for the treatment of one or more of thesediseases:

-   -   (1) pain conditions,    -   (2) pruritic conditions, and    -   (3) cough conditions.

In one embodiment, the pain condition is an acute pain or chronic paindisorder. In another embodiment, the pain condition is an acute paindisorder.

The compounds may be effective in treating nociception. Nociception orpain is essential for survival and often serves a protective function.However, the pain associated with surgical procedures and currenttherapies to relieve that pain, can delay recovery after surgery andincrease the length of hospital stays. As many as 80% of surgicalpatients experience post-operative pain due to tissue damage, and damageto peripheral nerves and subsequent inflammation. Approximately 10-50%of surgical patients will develop chronic pain after surgery oftenbecause the nerve damage results in lasting neuropathic pain once thewound has healed.

The compounds of structural formula I may be effective in treatingosteoarthritis. Osteoarthritis is type of arthritis caused byinflammation, breakdown, and eventual loss of cartilage in the joints.The standards of care for pain associated with osteoarthritis arenon-steroidal anti-inflammatory drugs (NSAIDs), for example celecoxiband diclofenac (reviewed in Zeng et al., 2018). Patients that do notrespond to NSAID therapies are typically treated with low dose opiates,such as hydrocodone. Patients that are refractory to the above therapieswill usually opt for total joint replacement.

The compounds of structural formula I may be effective in treatingperipheral neuropathy. Peripheral neuropathy is nerve damage caused bychronically high blood sugar and diabetes. It leads to numbness, loss ofsensation, and sometimes pain in distal limbs such as feet, legs, orhands. It is the most common complication of diabetes. The standards ofcare for the treatment of painful diabetic neuropathy aregabapentinoids, for example gabapentin and pregabalin. Some patientswill respond well to tricyclic antidepressants such as amitriptyline,while other patients get significant relief using SRI/NRI drugs such asduloxetine (Schreiber et al., World J Diabetes. 2015 Apr. 15;6(3):432-44). Many options are available, however side-effects arecommon (e.g. dizziness, nausea) which limit their full potential.

The compounds of structural formula I may be effective in treatinginherited erythromelalgia. Inherited erythromelalgia (IEM) is a chronicpain syndrome which has been linked to mutations in severalvoltage-gated sodium channels, including Nav1.8 (Kist et al., PLoS One.2016 Sep. 6; 11(9):e0161789). Patients present with the classic “glovesand stocking” flare pattern on distal regions such as hands and feet,typically brought on with warm temperatures and exercise. Some patientsfind relief from the burning pain associated with flares by cold waterimmersion. Although medications that affect voltage-gated sodiumchannels (eg, lidocaine and mexiletine) show promise, there is nocurrent standard of care to treat IEM.

The compounds of structural formula I may be effective in treatingneuropathic pain. Neuropathic pain is pain caused by damage or diseaseaffecting the somatosensory nervous system. It has been demonstrated inhuman patients, as well as in animal models of neuropathic pain, thatdamage to primary afferent sensory neurons can lead to neuroma formationand spontaneous activity, as well as evoked activity in response tonormally innocuous stimuli. (Colloca et al., Nat Rev Dis Primers. 2017Feb. 16; 3:17002; Coward et al., Pain. 2000 March; 85(1-2):41-50;Yiangou et al., FEBS Lett. 2000 Feb. 11; 467(2-3):249-52; Carter et al.,Phys Med Rehabil Clin N Am. 2001 May; 12(2):447-59). Some nerve injuriesresult in an increase in Nav1.8 expression, which is believed to be anunderlying mechanism for pathological pain. (Black et al., Ann Neurol.2008 December; 64(6):644-53; Bird et al., Br J Pharmacol. 2015 May;172(10):2654-70). Injuries of the peripheral nervous system often resultin neuropathic pain persisting long after an initial injury resolves.Examples of neuropathic pain include, but are not limited to, postherpetic neuralgia, trigeminal neuralgia, diabetic neuropathy, chroniclower back pain, lumbar radiculopathy, phantom limb pain, pain resultingfrom cancer and chemotherapy, chronic pelvic pain, complex regional painsyndrome and related neuralgias, and painful conditions that arise dueto gain-of-function mutations in Nav1.8 (Huang et al., J Neurosci. 2013Aug. 28; 33(35):14087-97; Kist et al., PLoS One. 2016 Sep. 6;11(9):e0161789; Emery et al., J Neurosci. 2015 May 20; 35(20):7674-81;and Schreiber et al., World J Diabetes. 2015 Apr. 15; 6(3):432-44.

The ectopic activity of normally silent sensory neurons is thought tocontribute to the generation and maintenance of neuropathic pain, whichis generally assumed to be associated with an increase in sodium channelactivity in the injured nerve. (Wood et al., Curr Opin Pharmacol. 2001February; 1(1):17-21; Baker et al., TRENDS in Pharmacological Sciences,2001, 22(1): 27-31). Standards of care for neuropathic pain varyconsiderably depending on the particular condition, but first linetherapies are typically pregabalin, gabapentin, tricyclicantidepressants (e.g. amitriptyline), and SRI/NRI drugs (e.g.duloxetine). Patients refractory to these therapies are usuallyprescribed low dose opiates (e.g. hydrocodone).

The compounds of structural formula I may be effective in treatingmultiple sclerosis.

Recent evidence points to a potential role for Na_(v)1.8 in multiplesclerosis. Na_(v)1.8 expression in cerebellum has been identified intissues taken from animal models of multiple sclerosis (EAE model) andin postmortem brains from patients suffering from multiple sclerosis(MS) (Shields et al., Ann Neurol. 2012 February; 71(2):186-94; Black etal., Proc Natl Acad Sci U.S.A. 2000 Oct. 10; 97(21):11598-602). Also,two SCN10A polymorphisms showed significant association with MS(Roostaei et al., Neurology. 2016 Feb. 2; 86 (5):410-7). When Nav1.8 isoverexpressed in cerebellum, mice develop ataxic-related motor deficitswhich are ameliorated with oral delivery of a selective small moleculeNav1.8 antagonist (Shields et al., PLoS One. 2015 Mar. 6; 10(3)). Thesestudies suggest that a Nav1.8 antagonist may be a useful therapy totreat symptoms related to multiple sclerosis.

The compounds of structural formula I may be effective in treatingasthma. Asthma is caused by airway inflammation in which a person'sairways become hyper-responsive, narrow and swollen, which makes itdifficult to breathe. These symptoms are typically triggered through anallergic reaction (Nair P et al., J Allergy Clin Immunol Pract. 2017May-Jun.; 5(3):649-659). In a preclinical model of asthma, deletion ofNav1.8-containing neurons, or inhibition of nerve fibers via smallmolecules reduces airway inflammation and immune cell infiltration(Talbot et al., Neuron. 2015 Jul. 15; 87(2):341-54). Selective Nav1.8antagonists may be a useful therapy to prevent airway hypersensitivitycaused by immune cell infiltration.

The compounds of structural formula I may be effective in treatingpruritus. Pruritus, also commonly known as itch, affects approximately4% of the global population is an unpleasant sensation that elicits thedesire or reflex to scratch, and is regarded as closely related to pain(Luo et al., Cell Mol Life Sci. 2015 September; 72 (17): 3201-23).Theories on the origin of itch implicate the subtle, low-frequencyactivation of nociceptors (pain-sensing neurons); however, it has beendescribed that some afferents preferentially respond to histamine, whichinduces itch (Schmelz et al., J Neurosci. 1997 Oct. 15; 17(20):8003-8).At the same time, it has been found that histamine-responding neuronsalso respond to capsaicin which produces pain (McMahon et al., Trends inNeuroscience 1992, 15:497-501). Members of the transient receptorpotential (TRP) family, and nerve growth factor (NGF) are both known toplay a role in itch and pain, and clinically, both maladies are treatedwith therapeutic agents such as gabapentin and antidepressants.Therefore, it continues to be accepted that the underlying mechanisms ofpain and itch are highly interwoven and complex, and distinguishingpan-selective or itch-selective pathways remains ambiguous (Ikoma etal., Nat Rev Neurosci. 2006 July; 7(7):535-47). A role for Nav1.8 inpruritis was studied using a mouse transgenically expressing aconstitutively active form of the serine/threonine kinase BRAF wasexpressed in Nav1.8-expressing neurons. This resulted in enhancedpruriceptor excitability, and heightened evoked and spontaneousscratching behavior (Zhao et al., 2013). In skin, pruritogens arereleased from keratinocytes, lymphocytes, mast cells, and eosinophilsduring inflammation. These molecules act directly on free nerve endingswhich express Nav1.8 to induce itch (Riol-Blanco et al., Nature. 2014Jun. 5; 510 (7503):157-61). Chronic and acute itch can arise from manydifferent insults, diseases and disorders, and may be classified asdermal or pruriceptive, neurogenic, neuropathic, or psychogenic: itchcan arise from both systemic disorders, skin disorders, as well asphysical or chemical insult to the dermis. Pathologically, conditionssuch as dry skin, eczema, psoriasis, varicella zoster, urticaria,scabies, renal failure, cirrhosis, lymphoma, iron deficiency, diabetes,menopause, polycythemia, uremia, and hyperthyroidism can cause itch, ascan diseases of the nervous system such as tumors, multiple sclerosis,peripheral neuropathy, nerve compression, and delusions related toobsessive-compulsive disorders. Medicines such as opioids andchloroquine can also trigger itch (Ikoma et al., Nat Rev Neurosci. 2006Jul.; 7(7):535-47). Itching following burn is also an extremely seriousclinical problem as it hampers the healing process, resulting inpermanent scaring, and negatively impacting quality of life (Van Loey etal., Br J Dermatol. 2008 January; 158(1):95-100).

Also within the scope of this disclosure are pharmaceutically acceptablesalts of the compounds, and pharmaceutical compositions comprising thecompounds and a pharmaceutically acceptable carrier.

The compounds, or pharmaceutically acceptable salts thereof, may beuseful in treating pain conditions, pruritic conditions, and coughconditions.

A compound of structural formula I, or a pharmaceutically acceptablesalt thereof, may be used in the manufacture of a medicament for thetreatment of pain conditions, pruritic conditions, and cough conditionsin a human or other mammalian patient.

A method of treating a pain conditions comprises the administration of atherapeutically effective amount of a compound of structural formula I,or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising the compound, to a patient in need of treatment.A method of treating a pruritic condition comprises the administrationof a therapeutically effective amount of a compound of structuralformula I, or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising the compound, to a patient in needof treatment. A method of treating a cough condition comprises theadministration of a therapeutically effective amount of a compound ofstructural formula I, or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition comprising the compound, to a patient inneed of treatment. Other medical uses of the compounds of structuralformula I are described herein.

The term “pain condition” as used herein includes, but are not limitedto, acute pain, peri-operative pain, pre-operative pain, post-operativepain, neuropathic pain, post herpetic neuralgia, trigeminal neuralgia,diabetic neuropathy, chronic lower back pain, phantom limb pain, chronicpelvic pain, vulvodynia, complex regional pain syndrome and relatedneuralgias, pain associated with cancer and chemotherapy, painassociated with HIV, and HIV treatment-induced neuropathy, nerve injury,root avulsions, painful traumatic mononeuropathy, painfulpolyneuropathy, erythromyelalgia, paroxysmal extreme pain disorder,small fiber neuropathy, burning mouth syndrome, central pain syndromes(potentially caused by virtually any lesion at any level of the nervoussystem), postsurgical pain syndromes (e.g., post mastectomy syndrome,post thoracotomy syndrome, stump pain)), bone and joint pain(osteoarthritis), repetitive motion pain, dental pain, myofascial pain(muscular injury, fibromyalgia), perioperative pain (general surgery,gynecological), chronic pain, dysmennorhea, pain associated with angina,inflammatory pain of varied origins (e.g. osteoarthritis, rheumatoidarthritis, rheumatic disease, teno-synovitis and gout), shouldertendonitis or bursitis, gouty arthritis, and aolymyalgia rheumatica,primary hyperalgesia, secondary hyperalgesia, primary allodynia,secondary allodynia, or other pain caused by central sensitization,complex regional pain syndrome, chronic arthritic pain and relatedneuralgias acute pain, migraine, migraine headache, headache pain,cluster headache, non-vascular headache, traumatic nerve injury, nervecompression or entrapment, and neuroma pain,

The term “pruritic condition” or “pruritic disorder” as used hereinincludes, but is not limited to, conditions with an unpleasant sensationthat provokes the desire to scratch, such as chronic itch.

The term “cough condition” or “cough disorder” as used herein includes,but is not limited to, chronic cough, neuropathic cough or cough due toneurological conditions.

Treatment of a disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors refers to theadministration of the compounds of structural formula I to a subjectwith the disease, disorder or condition. One outcome of treatment may bereducing the disease, disorder or condition mediated by Na_(v)1.8 sodiumion channel activity or Na_(v)1.8 receptors. Another outcome oftreatment may be alleviating the disease, disorder or condition mediatedby Na_(v)1.8 sodium ion channel activity or Na_(v)1.8 receptors. Anotheroutcome of treatment may be ameliorating the disease, disorder orcondition mediated by Na_(v)1.8 sodium ion channel activity or Na_(v)1.8receptors. Another outcome of treatment may be suppressing the disease,disorder or condition mediated by Na_(v)1.8 sodium ion channel activityor Na_(v)1.8 receptors. Another outcome of treatment may be managing thedisease, disorder or condition mediated by Na_(v)1.8 sodium ion channelactivity or Na_(v)1.8 receptors.

Another outcome of treatment may be preventing the disease, disorder orcondition mediated by Na_(v)1.8 sodium ion channel activity or Na_(v)1.8receptors.

Prevention of the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors refers to theadministration of the compounds of the present disclosure to a subjectat risk of the disease, disorder or condition. One outcome of preventionmay be reducing the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors in a subject at riskof the disease, disorder or condition. Another outcome of prevention maybe suppressing the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors in a subject at riskof the disease, disorder or condition. Another outcome of prevention maybe ameliorating the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors in a subject at riskof the disease, disorder or condition. Another outcome of prevention maybe alleviating the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors in a subject at riskof the disease, disorder or condition. Another outcome of prevention maybe managing the disease, disorder or condition mediated by Na_(v)1.8sodium ion channel activity or Na_(v)1.8 receptors in a subject at riskof the disease, disorder or condition.

One outcome of treatment may be reducing the amount of pain experiencedby a subject relative to that subject's pain immediately before theadministration of the compounds of structural formula I. Another outcomeof treatment may be alleviating the amount of pain experienced by asubject relative to that subject's pain immediately before theadministration of the compounds of structural formula I. Another outcomeof treatment may be ameliorating the amount of pain experienced by asubject relative to that subject's pain immediately before theadministration of the compounds of structural formula I. Another outcomeof treatment may be suppressing the amount of pain experienced by asubject relative to that subject's pain immediately before theadministration of the compounds of structural formula I. Another outcomeof treatment may be managing the amount of pain experienced by a subjectrelative to that subject's pain immediately before the administration ofthe compounds of structural formula I. Another outcome of treatment maybe ameliorating the amount of pain experienced by a subject relative tothat subject's pain immediately before the administration of thecompounds of structural formula I.

Another outcome of treatment may be preventing further pain experiencedby a subject after the administration of the compounds of structuralformula I.

Prevention of pain refers to the administration of the compounds ofstructural formula I to reduce the pain of a subject at risk of pain.Prevention includes, but is not limited to, the administration to asubject prior to surgery or other expected painful event. One outcome ofprevention may be reducing pain in a subject at risk of pain. Anotheroutcome of prevention may be suppressing pain in a subject at risk ofpain. Another outcome of prevention may be ameliorating pain in asubject at risk of pain. Another outcome of prevention may bealleviating pain in a subject at risk of pain. Another outcome ofprevention may be managing pain in a subject at risk of pain.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of structural formula I or aprodrug thereof to the individual or mammal in need of treatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to themammal in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods provided herein isdetermined via the use of well known risk factors. The effective amountof an individual compound is determined, in the final analysis, by thephysician or veterinarian in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration other drugs and treatments which the patient mayconcomitantly require, and other factors in the physician's judgment.

The usefulness of the present compounds in these diseases or disordersmay be demonstrated in animal disease models that have been reported inthe literature.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound ofstructural formula I. For example, oral, intravenous, infusion,subcutaneous, transcutaneous, intramuscular, intradermal, transmucosal,intramucosal, rectal, topical, parenteral, ocular, pulmonary, nasal, andthe like may be employed. Dosage forms include tablets, troches,dispersions, suspensions, solutions, capsules, creams, ointments,aerosols, and the like. Preferably compounds of structural formula I areadministered orally.

In the treatment or prevention of disorders, diseases and/or conditionswhich require inhibition of Na_(v)1.8 sodium ion channel activity, asuitable dosage level will generally be about 0.0001 to 500 mg per kgpatient body weight per day which can be administered in single ormultiple doses. In one embodiment, a suitable dosage level may be about0.001 to 500 mg per kg patient body weight per day. In anotherembodiment, a suitable dosage level may be about 0.001 to about 250mg/kg per day. In another embodiment, a suitable dosage level may beabout 0.01 to about 250 mg/kg per day. In another embodiment, a suitabledosage level may be about 0.1 to about 100 mg/kg per day. In anotherembodiment, a suitable dosage level may be about 0.05 to 100 mg/kg perday. In another embodiment, a suitable dosage level may be about 0.1 to50 mg/kg per day. In another embodiment, a suitable dosage level may beabout 0.05 to 0.5 mg/kg per day. In another embodiment, a suitabledosage level may be about 0.5 to 5 mg/kg per day. In another embodiment,a suitable dosage level may be about 5 to 50 mg/kg per day. For oraladministration, the compositions are preferably provided in the form oftablets containing 0.01 to 1000 mg of the active ingredient,particularly 0.01, 0.025, 0.05, 0.075, 0.1, 0.25, 0.5, 0.75, 1.0, 2.5,5.0, 7.5, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. The compounds may be administered on aregimen of 1 to 8 times per day; preferably, 1 to 4 times a day; morepreferably once or twice per day. This dosage regimen may be adjusted toprovide the optimal therapeutic response.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The compounds of structural formula I may be used in pharmaceuticalcompositions comprising (a) the compound(s) or pharmaceuticallyacceptable salts thereof, and (b) a pharmaceutically acceptable carrier.The compounds of structural formula I may be used in pharmaceuticalcompositions that include one or more other active pharmaceuticalingredients. The compounds of this disclosure may also be used inpharmaceutical compositions in which the compound of structural formulaI or a pharmaceutically acceptable salt thereof is the only activeingredient.

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions disclosed herein encompass any compositionmade by admixing a compound of structural formula I and apharmaceutically acceptable carrier.

Compounds of structural formula I may be used in combination with otherdrugs that may also be useful in the treatment or amelioration of thediseases or conditions for which compounds of structural formula I areuseful. Such other drugs may be administered, by a route and in anamount commonly used therefor, contemporaneously or sequentially with acompound of structural formula I. In the treatment of patients who havepain conditions, pruritic conditions and cough conditions, more than onedrug is commonly administered. The compounds of Formula I may generallybe administered to a patient who is already taking one or more otherdrugs for these conditions. Often the compounds will be administered toa patient who is already being treated with one or more anti-paincompounds when the patient's pain is not adequately responding totreatment.

The combination therapy also includes therapies in which the compound ofstructural formula I and one or more other drugs are administered ondifferent overlapping schedules. It is also contemplated that when usedin combination with one or more other active ingredients, the compoundof structural formula I and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions disclosed herein include those that containone or more other active ingredients, in addition to a compound ofstructural formula I.

Examples of other active ingredients that may be administered incombination with a compound of structural formula I, and eitheradministered separately or in the same pharmaceutical composition,include but are not limited to:

-   -   (i) an opioid agonist;    -   (ii) an opioid antagonist;    -   (iii) a calcium channel antagonist;    -   (iv) a NMDA receptor agonist;    -   (v) a NMDA receptor antagonist;    -   (vi) a COX-2 selective inhibitor;    -   (vii) a NSAID (non-steroidal anti-inflammatory drug);    -   (viii) an analgesic;    -   (ix) a sodium channel inhibitor;    -   (x) an anti-NGF antibody;    -   (xi) a Na_(v)1.7 inhibitor;    -   (xii) a HCN inhibitor;    -   (xiii) a TRPV1 antagonist;    -   (xiv) a Na_(v)1.7 biological; and    -   (xv) a Na_(v)1.8 biological; and        pharmaceutically acceptable salts thereof.

In another embodiment, the pharmaceutical composition comprises:

-   -   (1) compound of Claim 1 or a pharmaceutically acceptable salt        thereof;    -   (2) one or more compounds, or pharmaceutically acceptable salts        thereof, selected from the group consisting of:    -   (i) an opioid agonist;    -   (ii) an opioid antagonist;    -   (iii) a calcium channel antagonist;    -   (iv) a NMDA receptor agonist;    -   (v) a NMDA receptor antagonist;    -   (vi) a COX-2 selective inhibitor;    -   (vii) a NSAID (non-steroidal anti-inflammatory drug);    -   (viii) an analgesic;    -   (ix) a sodium channel inhibitor;    -   (x) an anti-NGF antibody;    -   (xi) a Na_(v)1.7 inhibitor;    -   (xii) a HCN inhibitor;    -   (xiii) a TRPV1 antagonist;    -   (xiv) a Na_(v)1.7 biological; and    -   (xv) a Na_(v)1.8 biological; and        pharmaceutically acceptable salts thereof; and    -   (3) a pharmaceutically acceptable carrier.

A Na_(v) 1.7 biological means a protein, including, but not limited to,antibodies, nanobodies and peptides, that inhibits the function of theNa_(v)1.7 channel. A Na_(v) 1.8 biological means a protein, including,but not limited to, antibodies, nanobodies and peptides, that inhibitsthe function of the Na_(v)1.8 channel.

Specific compounds of use in combination with a compound of structuralformula I include: sodium channel inhibitors, including but not limitedto, lidocaine including the lidocaine patch; tricyclic antidepressantsincluding, but not limited to, amitriptyline; and SRI/NRI drugs,including but not limited to, duloxetine.

Suitable opioid agonists include, but are not limited to, codeine,fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine,methadone, morphine, oxycodone, oxymorphone, buprenorphine, butorphanol,dezocine, nalbuphine, pentazocine, and tramadol.

Suitable opioid antagonists include, but are not limited to, naltrexoneand naloxone.

Suitable calcium channel antagonists include, but are not limited to,Amlodipine, Diltiazem, Felodipine, gabapentin, Isradipine, Nicardipine,Nifedipine, Nisoldipine, pregabalin, Verapamil, and ziconitide.

Suitable NMDA receptor antagonists include, but are not limited to,ketamine, methadone, memantine, amantadine, and dextromethorphan.

Suitable COX-2 inhibitors include, but are not limited to, celecoxib,etoricoxib and parecoxib.

Suitable NSAIDs or non-steroidal anti-inflammatory drugs include, butare not limited to, aspirin, diclofenac, diflunisal, etodolac,fenoprofin, flurbiprofen, ibuprofen, indomethacin, ketoprofen,meclofenamic acid, mefenamic acid, meloxicam, naproxen, naproxen sodium,oxaprozin, piroxicam, sulindac, and tolmetin.

Suitable analgesics include, but are not limited to, acetaminophen andduloxetine.

The above combinations include combinations of a compound of structuralformula I not only with one other active compound, but also with two ormore other active compounds. Non-limiting examples include combinationsof compounds with two or more active compounds selected from: opioidagonists; opioid antagonists; calcium channel antagonists; NMDA receptoragonists; NMDA receptor antagonists; COX-2 selective inhibitors; NSAIDs(non-steroidal anti-inflammatory drugs); and an analgesic.

The compounds of structural formula I, or a pharmaceutically acceptablesalt thereof, may also be used in combination with spinal cordstimulation therapy and cutaneous stimulation therapy.

Also provided is a method for the treatment or prevention of a Na_(v)1.8sodium ion channel activity mediated disease, disorder or condition,which method comprises administration to a patient in need of suchtreatment or at risk of developing a Na_(v)1.8 sodium ion channelactivity mediated disease with a therapeutically effective amount of aNa_(v)1.8 sodium ion channel activity inhibitor and an amount of one ormore active ingredients, such that together they give effective relief.

In a further aspect, there is provided a pharmaceutical compositioncomprising a Na_(v)1.8 sodium ion channel activity inhibitor and one ormore active ingredients, together with at least one pharmaceuticallyacceptable carrier or excipient.

Thus, there is provided the use of a Na_(v)1.8 sodium ion channelactivity inhibitor and one or more active ingredients for themanufacture of a medicament for the treatment or prevention of aNa_(v)1.8 sodium ion channel activity mediated disease, disorder orcondition. In a further or alternative aspect of the present disclosure,there is therefore provided a product comprising a Na_(v)1.8 sodium ionchannel activity inhibitor and one or more active ingredients as acombined preparation for simultaneous, separate or sequential use in thetreatment or prevention of a Na_(v)1.8 sodium ion channel activitymediated disease, disorder or condition. Such a combined preparation maybe, for example, in the form of a twin pack.

It will be appreciated that for the treatment or prevention of painconditions, pruritic conditions and cough conditions, a compound ofstructural formula I may be used in conjunction with anotherpharmaceutical agent effective to treat that disease, disorder orcondition.

Also provided is a method for the treatment or prevention of painconditions, pruritic conditions and cough conditions, which methodcomprises administration to a patient in need of such treatment anamount of a compound of structural formula I and an amount of anotherpharmaceutical agent effective to threat that disorder, disease orcondition, such that together they give effective relief.

Further provided is a method for the treatment or prevention of painconditions, pruritic conditions and cough conditions, which methodcomprises administration to a patient in need of such treatment anamount of a compound of structural formula I and an amount of anotherpharmaceutical agent useful in treating that particular condition,disorder or disease, such that together they give effective relief.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a cell, tissue, system, animal or human that isbeing sought by the researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disorderbeing treated. The novel methods of treatment provided herein are fordisorders known to those skilled in the art. The term “mammal” includeshumans, and companion animals such as dogs and cats.

The weight ratio of the compound of structural formula I to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of structural formula I is combinedwith a COX-2 inhibitor the weight ratio of the compound of structuralformula I to the COX-2 inhibitor will generally range from about 1000:1to about 1:1000, preferably about 200:1 to about 1:200. Combinations ofa compound of structural formula I and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used.

Methods of Synthesis

The following reaction schemes and Examples illustrate methods which maybe employed for the synthesis of the compounds of structural formula Idescribed herein. These reaction schemes and Examples are provided forillustration and are not to be construed as limiting the invention inany manner. All substituents are as defined above unless indicatedotherwise. Several strategies based upon synthetic transformations knownin the literature of organic synthesis may be employed for thepreparation of the compounds of structural formula I.

Instrumentation

Reverse phase chromatography was carried out on a Gilson GX-281 equippedwith a column selected from the following: Phenomenex Synergi C18 (150mm×30 mm×4 micron), YMC-Actus Pro C18 (150 mm×30 mm×5 micron), XtimateC18 (150 mm×25 mm×5 micron), Boston Green ODS (150 mm×30 mm×5 micron),XSELECT C18 (150 mm×30 mm×5 micron), and Waters XSELECT C18 (150 mm×30mm×5 micron). Conditions included either high pH (0-100%acetonitrile/water eluent comprising 0.1% v/v 10 mM NH₄CO₃ or 0.05%NH₄OH) or low pH (0-95% acetonitrile/water eluent comprising 0.1% v/vTFA) and are noted for some examples.

SFC chiral resolution was carried out on a Sepiate Prep SFC 100,Multigram II (MG II), THAR80 prep SFC, or a Waters SFC (80, 200, or350).

LC/MS determinations were carried out on a Waters Classing Aquity systemequipped with UV and MS detectors and a Waters SQD mass spectrometer, aShimadzu 20 UV 254 and 220 nM with Shimadzu 2010 or 2020 massspectrometer, or an Agilent 1200 HPLC quipped with DAD/ELSD and G6110MSD using one of the following conditions: 1) Ascentis Express C18 (3×50mm) 2.7 μm column using mobile phase containing A: 0.05% TFA in waterand B: 0.05% TFA in acetonitrile with a gradient from 90:10 (A:B) to5:95 (A:B) over 6 min at a flow rate of 1.8 mL/min, UV detection at 210nm; 2) Aquity BEH C18, (1.0×50 mm) 1.7 μm column using mobile phasecontaining A: 0.05% TFA in water and B: 0.05% TFA in acetonitrile with agradient from 90:10 (A:B) to 5:95 (A:B) over 2 min at a flow rate of 0.3mL/min, UV detection at 215 nm; 3) Agilent YMC J′Sphere H-80 (3×50 mm) 5μm column using mobile phase containing A: 0.1% TFA in water and B:acetonitrile with a gradient from 95:5 (A:B) to 0:100 (A:B) over 3.6 minand 0:100 (A:B) for 0.4 min at a flow rate of 1.4 mL/min, UV detectionat 254 and 220 nm and Agilent 1100 quadrupole mass spectrometer; 4) anAgilent TC-C18 (2.1×50 mm) 5 μm column using mobile phase containing A:0.0375% TFA in water and B: 0.01875% TFA in acetonitrile with a gradientfrom 90:10 (A:B) for 0.4 min to 90:10 to 0:100 (A:B) over 3 min and10:90 (A:B) for 0.6 min at a flow rate of 0.8 mL/min, UV detection at254 and 220 nm and Agilent 6110 quadrupole mass spectrometer.

Proton or 1H NMR was acquired using a Varian Unity-Inova 400 MHz NMRspectrometer equipped with a Varian 400 ATB PFG 5 mm, Nalorac DBG 400-5or a Nalorac IDG 400-5 probe, a Varian-400 MHz MR spectrometer equippedwith an Auto X ID PFG Probe 5 mm, a Varian 400 MHz VNMRS spectrometerequipped with a PFG 4Nuc Probe 5 mm, or a Bruker AvanceIII 500 MHzspectrometer equipped with a PABBO Probe 5 mm in accordance withstandard analytical techniques, unless specified otherwise, and resultsof spectral analysis are reported. Chemical shift (6) values arereported in delta (6) units, parts per million (ppm). Chemical shiftsfor 1H NMR spectra are given relative to signals for residualnon-deuterated solvent (CDCl₃ referenced at δ 7.26 ppm; DMSO d-6referenced at δ 2.50 ppm and CD₃OD referenced at δ 3.31 ppm). Multiplesare reported by the following abbreviations: s=singlet, d=doublet,t=triplet, q=quartet, dd=doublet of doublets, m=multiplet or overlap ofnonequivalent resonances. Coupling constants (J) are reported in Hertz(Hz).

Abbreviations

AcOH is acetic acid; Boc is tert-butoxycarbonyl; Calc'd is calculated;CDI is 1,1′-carbonyldiimidazole, DAST is diethylaminosulfur trifluoride;DCE is dichloroethane; DCM is dichloromethane; DEA is diethanolamine;DIBAL-H is diisobutylaluminum hydride; DIPEA or DIEA isN,N-diisopropylethylamine; DMA is dimethylacetamide; DMF isdimethylformamide; DMSO is dimethylsulfoxide; dppf is1,1′-bis(diphenylphosphino)ferrocene; EDC is1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EDCI is1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; Et₂O is diethyl ether;EtOAc is ethyl acetate; EtOH is ethanol; Et₃N or NEt₃ is triethyl amine;g is grams; h or hr(s) is hour(s); HATU is1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluoro-phosphate;Hex is hexanes; HOAt is 1-Hydroxy-7-azabenzotriazole; HPLC ishigh-performance liquid chromatography; IPA is isopropyl alcohol;iPrMgCl or i-PrMgCl is isopropylmagnesium chloride; iPrMgCl-LiCl isisopropylmagnesium chloride lithium chloride complex; L is liter; LAH islithium aluminum hydride; LC/MS is liquid chromatography/massspectrometry; LRMS is low resolution mass spectrometry; M is molar; Meis methyl; MeOH is methanol; MeCN is acetonitrile; MeMgBr ismethylmagnesium bromide; mg is milligrams; mL is milliliter; mmol ismillimole(s); Ms-Cl is methanesulfonyl Chloride; N is normal; NaHMDS isSodium bis(trimethylsilyl)amide; NH₄OAc is ammonium acetate, NMO is4-Methylmorpholine N-oxide; NMP is N-methylpyrrolidone; mPa ismillipascal(s); mol % is mole percent; PCC is pyridiniumchloro-chromate; Pd/C is palladium on carbon; Pd(dppf)Cl₂ is[1,1-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II); Pd(PPh₃)₄is tetrakis(triphenyl-phosphine)-palladium(O); Pd(tBu₃P)₂ isBis(tri-tert-butylphosphine)-palladium(O); pet. ether or PE is petroleumether; PG is protecting group; PPh₃ is triphenyl-phosphine; ppm ismilligrams per liter; Prep. or prep is preparative; psi is pounds persquare inch; rt or RT is room temperature; SFC is Supercritical FluidChromatography;s TBAF is tetrabutylammonium fluoride; tBuXPhos Pd G3 is[(2-Di-tert-butylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methane-sulfonate; TEA is triethylamine; TFA is trifluoroacetic acid; THF is tetrahydrofuran; Ti(OEt)₄ is titanium (IV) ethoxide;Ti(OiPr)₄ is titanium (IV) isopropoxide; TLC is thin layerchromatography; UV is ultraviolet; and v/v is volume per volume.

As illustrated in Scheme A, compounds of structural formula I can beprepared by condensation between an appropriately functionalizedaldehyde A-1 and tert-butanesulfinamide, utilizing dehydrating agentssuch as Ti(OEt)₄ or Ti(OiPr)₄, to afford intermediate A-2. IntermediateA-2 can then be reacted with a variety of organometallic nucleophilesA-3 to give intermediate A-4, which can be deprotected under acidicconditions to give amines of formula A-5. Amine A-5 can then be broughttogether with piperazine A-6 under urea coupling conditions (usingtriphosgene or CDI as coupling regents) to deliver compounds of formulaA-7. In some embodiments, a protecting group (such as Boc) may need tobe removed throughout the course of synthesis. Aldehydes of type A-1 andorganometallics of type A-3 are commercially available or may besynthesized from appropriate starting materials and reagents.

As illustrated in Scheme B, the compounds of structural formula I can beprepared by activation of appropriately functionalized carboxylic acidB-1 with either (COCl)₂ or amide coupling with amine B-2 to giveintermediate B-3. This intermediate is then suitable to for reactionwith a variety of organometallic nucleophiles A-3 to give intermediateB-4. Intermediate B-4 can then undergo reductive amination reaction inthe presence of an amine source and reductant to yield intermediate A-5.In some cases, tert-butanesulfinamide was used as the amine source andwould require deprotection (in an acidic environment) followingreductive amination. Amine A-5 can then be brought together withpiperazine A-6 under urea coupling conditions (using triphosgene or CDIas coupling regents) to deliver compounds of formula A-7. In someembodiments, a protecting group, such as Boc, may need to be removedthroughout the course of synthesis. Carboxylic acids of type B-1 andorganometallics of type A-3 are commercially available or may besynthesized from appropriate starting materials and reagents.

EXAMPLES Examples 1A and 1BN—((R)-3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamideandN—((S)-3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)-methyl)-3-oxopiperazine-1-carboxamide

Step 1:(3-chloro-4-fluorophenyl)(-4-(trifluoromethyl)cyclohexyl)methanone To asolution of trans-4-(trifluoromethyl)cyclohexanecarboxylic acid (571 mg,2.91 mmol) in CH₂Cl₂ (5 mL) at 0° C. was added oxalyl chloride in DCM (2M, 3.64 mL, 7.28 mmol) and one drop of DMF. The mixture was warmed toRT, stirred for 4 hours, then heated to 40° C. and stirred for 30minutes. The mixture was then concentrated under reduced pressure togive a residue, which was dissolved in THF (4 mL, solution A). In adifferent flask, copper(I) cyanide (652 mg, 7.28 mmol) was suspended inTHF (4 mL) and cooled to 0° C., followed by the addition of3-chloro-4-fluorophenylmagnesium bromide in THF (0.5 M, 11.64 mL, 5.82mmol). The mixture was stirred at 0° C. for 1 hour, then solution A wasadded and the mixture was stirred at 0° C. for 4 hours. The reaction wasquenched with 30 ml of saturated aqueous NH₄Cl and extracted with ethylacetate (2×30 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give the titlecompound. LCMS m z (M+H): calculated 308.7, observed 309.2.

Step 2:(3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methanamineA microwave tube was charged with(3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl) cyclohexyl)methanone(1281 mg, 4.15 mmol), ammonium acetate (2559 mg, 33.2 mmol) and ethanol(15 mL). The mixture was microwaved at 130° C. for 20 minutes and cooledto RT, followed by the addition of sodium cyanoborohydride (287 mg, 4.56mmol). The reaction mixture was microwaved at 125° C. for 20 minutes andthen cooled to RT. The reaction was quenched by the addition of 10%aqueous K₂CO₃ (30 mL), and extracted with ethyl acetate (2×30 mL). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound. LCMS m/z(M+H): calculated 413.9, observed 414.4.

Step 3: Examples 1A and 1B To a solution of(3-chloro-4-fluorophenyl)(trans-4-(trifluoro-methyl)cyclohexyl)methanamine(333 mg, 1.075 mmol) in DCM (3 mL) at 0° C. was added Et₃N (0.749 mL,5.38 mmol) and triphosgene (319 mg, 1.075 mmol). The mixture was stirredat 0° C. for 1 hour and then piperazin-2-one (215 mg, 2.150 mmol) wasadded. After stirring at 0° C. for 1 hour, the reaction was warmed toRT, stirred at RT for 1 hour, and then concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel, eluting with (0-4% MeOH/DCM) to give a mixture of isomers,which was further separated by SFC (OD-H column, 25% EtOH+0.25% DIPEAco-solvent) to give Examples 1A (second eluted fraction) and 1B (firsteluted fraction)

Example 1A: LRMS m/z (M+H): calculated 435.8, observed 436.4. ¹H NMR δ(ppm) (500 MHz, DMSO-d6): 8.01 (s, 1H), 7.53 (dd, J=7.3, 2.0 Hz, 1H),7.35 (t, J=8.9 Hz, 1H), 7.32-7.27 (m, 1H), 6.88 (d, J=8.6 Hz, 1H), 4.37(t, J=9.1 Hz, 1H), 3.96-3.77 (m, 2H), 3.54-3.41 (m, 2H), 3.14 (td,J=5.3, 2.6 Hz, 2H), 2.19 (d, J=8.6 Hz, 1H), 2.06 (d, J=12.5 Hz, 1H),1.93 (d, J=12.4 Hz, 1H), 1.78 (d, J=12.7 Hz, 1H), 1.65 (q, J=11.8 Hz,1H), 1.28-0.87 (m, 5H). Example 1B: LRMS m/z (M+H): calculated 435.8,observed 436.4. ¹H NMR δ (ppm) (500 MHz, DMSO-d6): 8.01 (s, 1H), 7.53(dd, J=7.3, 2.0 Hz, 1H), 7.38-7.26 (m, 2H), 6.87 (d, J=8.6 Hz, 1H),4.44-4.31 (m, 1H), 4.00-3.80 (m, 2H), 3.57-3.42 (m, 2H), 2.51 (p, J=1.8Hz, 2H), 2.25-2.13 (m, 1H), 2.08 (s, 1H), 1.93 (d, J=11.9 Hz, 1H),1.83-1.74 (m, 1H), 1.71-1.57 (m, 1H), 1.27-0.94 (m, 5H).

TABLE 1 The following examples were prepared according to the syntheticprocedure for Examples 1A and 1B, using the appropriate startingmaterials and reagents. Calc'd Observed Example Compound Name [M + H]⁺[M + H]⁺ Conditions 2A

N-((R or S)-(3- chloro-4-fluoro- phenyl)(8,8-difluoro-bicyclo[3.2.1]octan- 3-yl)methyl)-3- oxopiperazine-1- carboxamide 429.8430.4 SFC: OD-H Co-solvent: 25% (IPA + 0.2% DIPEA) peak 1 2B

N-((S or R)-(3- chloro-4-fluoro- phenyl)(8,8-difluroo-bicyclo[3.2.1]octan- 3-yl)methyl)-3- oxopiperazine-1- carboxamide 429.8430.4 SFC: OD-H Co-solvent 25% (IPA + 0.2% DIPEA) peak 2 3A

(2R)-N-((R or S)-(3- chloro-4-fluoro- phenyl)(8,8-difluoro-bicyclo[3.2.1]octan- 3-yl)methyl)-2- methyl-3-oxo- piperazine-1-carboxamide 443.9 444.4 SFC: OJ-H Co-solvent: 20% MeOH peak 1 3B

(2R)-N-((S or R)-(3- chloro-4-fluoro- phenyl)(8,8-difluoro-bicyclo[3.2.1]octan- 3-yl)methyl)-2- methyl-3-oxo- piperazine-1-carboxamide 443.9 444.4 SFC: OJ-H Co-solvent: 20% MeOH peak 2 4A

N-((R or S)-(4- chlorophenyl)(trans- 4-(trifluoromethyl)-cyclohexyl)methyl)- 3-oxopiperazine-1- carboxamide 417.8 418.4 SFC: OJ-HCo-solvent: 30% (MeOH/ CH3CN 1:1) peak 2 4B

N-((S or R)-(4- chlorophenyl)(trans- 4-(trifluoromethyl)-cyclohexyl)methyl)- 3-oxopiperazine-1- carboxamide 417.8 418.4 SFC: OJ-HCo-solvent: 30% (MeOH/ CH₃CN 1:1) peak 1 5A

(2R)-N-((R or S)-(3- chloro-4-fluoro- phenyl)(trans-4-(trifluoromethyl)cyclo- hexyl)methyl)-2- methyl-3-oxo- piperazine-1-carboxamide 449.8 450.4 SFC: OJ-H Co-solvent: 30% (MeOH/ CH₃CN 1:1) peak1 5B

(2R)-N-((S or R)-(3- chloro-4-fluoro- phenyl)(trans-4-(tri-fluoromethyl)cyclo- hexyl)methyl)-2- methyl-3-oxo- piperazine-1-carboxamide 449.8 450.4 SFC: OJ-H Co-solvent: 30% (MeOH/ CH₃CN 1:1):peak 2 6A

(R)-2-methyl-3-oxo- N-((R or S)-(trans-4- (trifluoromethyl)cyclo-hexyl)(3,4,5-tri- fluorophenyl)methyl) piperazine-1- carboxamide 451.4452.3 SFC: OJ-H Co-solvent: 25% EtOH peak 1 6B

(R)-2-methyl-3-oxo- N-((S or R)-(trans-4- (trifluoromethyl)cyclo-hexyl)(3,4,5-tri- fluorophenyl)methyl) piperazine-1- carboxamide 451.4452.3 SFC: OJ-H Co-solvent: 25% EtOH peak 2 7A

(2R)-N-((R or S)-(3- chloro-4-fluoro- phenyl)((1R,3s,5S)- 6,6-difluoro-bicyclo[3.1.0]hexan- 3-yl)methyl)-2- methyl-3-oxo- piperazine-1-carboxamide 415.8 416.3 SFC: OJ-H Co-solvent: 30% (EtOH + 0.2% DIPEA)peak 1 7B

(2R)-N-((S or R)-(3- chloro-4-fluoro- phenyl)((1R,3s,5S)- 6,6-difluoro-bicyclo[3.1.0]hexan- 3-yl)methyl)-2- methyl-3-oxo- piperazine-1-carboxamide 415.8 416.3 SFC: OJ-H Co-solvent: 30% (EtOH + 0.2% DIPEA)peak 1 8A

(2R)-N-((R or S)- (3,4-difluoro- phenyl)(trans-4-(trifluoromethyl)cyclo- hexyl)methyl)-2- methyl-3-oxo- piperazine-1-carboxamide 433.4 434.4 SFC: OJ-H Co-solvent: 30% EtOH peak 1 8B

(2R)-N-((S or R)- (3,4-difluoro- phenyl)(trans-4-(trifluoromethyl)cyclo- hexyl)methyl)-2- methyl-3-oxo- piperazine-1-carboxamide 433.4 434.4 SFC: OJ-H Co-solvent: 30% EtOH peak 2 9A

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(trans-4-(trifluoromethyl)cyclo- hexyl)methyl)-2- methyl-3-oxo- piperazine-1-carboxamide 467.9 468.4 SFC: OJ-H Co-solvent: 15% EtOH peak 1 9B

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(trans-4-(trifluoromethyl)cyclo- hexyl)methyl)-2- methyl-3-oxo- piperazine-1-carboxamide 467.9 468.4 SFC: OJ-H Co-solvent: 15% EtOH peak 2 10A

N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(trans-4-(trifluoromethyl)cyclo- hexyl)methyl)-3- oxopiperazine-1- carboxamide453.8 454.4 SFC: OJ-H Co-solvent: 15% EtOH peak 1 10B

N-((S or R)-(3- chloro-2,4-di- fluorophenyl)(trans- 4-(trifluoromethyl)-cyclohexyl)methyl)- 3-oxopiperazine-1- carboxamide 453.8 454.4 SFC: OJ-HCo-solvent: 15% EtOH peak 2 11A

(R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)((1R,3s,5S)-6,6-difluoro- bicyclo[3.1.0]hexan- 3-yl)methyl)-2- methyl-3-oxo-piperazine-1- carboxamide 433.8 434.3 SFC: OJ-H Co-solvent: 25% EtOHpeak 1 11B

(R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)((1R,3s,5S)-6,6-difluoro- bicyclo[3.1.0]hexan- 3-yl)methyl)-2- methyl-3-oxo-piperazine-1- carboxamide 433.8 434.3 SFC: OJ-H Co-solvent: 25% EtOHpeak 2 12A

N-((R or S)-(3- chloro-4-fluoro- phenyl)(4-(trifluoro-methyl)bicyclo[2.2.2] octan-1-yl)methyl)-3- oxopiperazine-1- carboxamide461.9 462.4 SFC: AD-H Co-solvent: 25% MeOH + 0.2% DIPEA peak 1 12B

N-((S or R)-(3- chloro-4-fluoro- phenyl)(4-(trifluoro-methyl)bicyclo[2.2.2] octan-1-yl)methyl)-3- oxopiperazine-1- carboxamide461.9 462.4 SFC: AD-H Co-solvent: 25% MeOH + 0.2% DIPEA peak 2 13A

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(4,4-difluoro-cyclohexyl)methyl)- 2-methyl-3-oxo- piperazine-1- carboxamide 435.1436.2 SFC: AS-H Co-solvent: 45% EtOH + 0.1% NH₃H₂O peak 1 13B

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(4,4-difluoro-cyclohexyl)methyl)- 2-methyl-3-oxo- piperazine-1- carboxamide 435.1436.2 SFC: AS-H Co-solvent: 45% EtOH + 0.1% NH₃H₂O peak 2 14A

(2R)-N-((R or S)-(3- chloro-4-fluoro- phenyl)(4,4-difluoro-cyclohexyl)methyl)- 2-methyl-3-oxo- piperazine-1- carboxamide 417.1418.2 SFC: AS-H Co-solvent: 45% EtOH + 0.1% NH₃H₂O peak 1 14B

(2R)-N-((S or R)-(3- chloro-4-fluoro- phenyl)(4,4-difluoro-cyclohexyl)methyl)- 2-methyl-3-oxo- piperazine-1- carboxamide 417.1418.2 SFC: AS-H Co-solvent: 45% EtOH + 0.1% NH₃H₂O peak 2

Examples 15A and 15B(2R)—N—((R)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamideand(2R)—N—((S)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide

Step 1: 1-(2,2,2-trifluoroethyl)piperidine-4-carbonitrile To a solutionof 4-cyanopiperidine (517 mg, 4.69 mmol) in anhydrous CH₂Cl₂ (8 mL) wasadded 2,2,2-trifluoroethyltrifluoromethane-sulfonate (0.744 mL, 5.16mmol) and Et₃N (0.850 mL, 6.10 mmol). The mixture was stirred at RT for3 days and then partitioned between diethyl ether and saturated aqueousNaHCO₃. The separated organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound. LRMS m z(M+H): calculated 192.2, observed 193.1.

Step 2:(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methanamineA microwave tube was charged with1-(2,2,2-trifluoroethyl)piperidine-4-carbonitrile (380 mg, 1.977 mmol),0.5 M 3-chloro-4-fluorophenyl magnesium bromide in THF (5.93 mL, 2.97mmol) and THF (3 mL). The mixture was microwaved at 100° C. for 15minutes and cooled to RT, followed by addition of MeOH (2 mL) and NaBH₄(224 mg, 5.93 mmol). The reaction was stirred at RT for 3 hours, thenquenched with saturated aqueous NH₄Cl (30 mL) and extracted with ethylacetate (2×30 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by column chromatography on silica gel, eluting with (0-5%MeOH/DCM) to give the title compound.

LRMS m/z (M+H): calculated 324.7, observed 325.2.

Step 3: Examples 15A and 15B To a solution of(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoro-ethyl)piperidin-4-yl)methanamine(150 mg, 0.462 mmol) in CH₂Cl₂ (3 mL) at 0° C. were added Et₃N (0.322mL, 2.309 mmol) and triphosgene (137 mg, 0.462 mmol). The mixture wasstirred at 0° C. for 1 hour and then (R)-3-methylpiperazin-2-one (105mg, 0.924 mmol) was added. After stirring at 0° C. for 1 hour, thereaction warmed to RT for 1 hour and concentrated under reducedpressure. The resulting residue was purified by column chromatography onsilica gel, eluting with (0-4% MeOH/DCM) to give a mixture, which wasfurther separated by SFC (OD-H column, 25% EtOH co-solvent) to giveexample 15A (first eluted fraction) and example 15B (second elutedfraction).

Example 15A: LRMS m/z (M+H): calculated 464.9, observed 465.4. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.31 (s, 1H), 7.15-7.10 (m, 2H), 6.54 (s,1H), 5.34 (s, 1H), 4.74 (d, J=6.5 Hz, 1H), 4.63 (d, J=6.8 Hz, 1H), 4.27(d, J=13.2 Hz, 1H), 3.48 (dt, J=11.6, 5.7 Hz, 1H), 3.30 (d, J=11.9 Hz,1H), 3.16-3.08 (m, 1H), 3.05 (d, J=10.5 Hz, 1H), 2.97 (q, J=9.6 Hz, 3H),2.30 (td, J=11.2, 3.3 Hz, 2H), 1.69 (d, J=25.0 Hz, 4H), 1.52 (d, J=7.0Hz, 3H).

Example 15B: LRMS m/z (M+H): calculated 464.9, observed 465.4. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.35 (d, J=6.7 Hz, 1H), 7.16-7.09 (m,2H), 6.07 (s, 1H), 5.10 (s, 1H), 4.61 (t, J=8.2 Hz, 1H), 4.44 (q, J=6.9Hz, 1H), 4.27 (d, J=12.8 Hz, 1H), 3.46 (td, J=11.5, 4.1 Hz, 1H), 3.30(d, J=12.0 Hz, 1H), 3.19-3.11 (m, 1H), 2.99 (tt, J=23.4, 12.5 Hz, 4H),2.41-2.26 (m, 2H), 1.82 (d, J=11.5 Hz, 1H), 1.64 (d, J=21.0 Hz, 4H),1.55 (d, J=7.0 Hz, 3H).

TABLE 2 The following examples were prepared according to the syntheticprocedure for examples 15A and 15B, using appropriate starting materialand reagents Calc'd Observed Example Compound Name [M + H]⁺ [M + H]⁺Conditions 16A

(2R)-N-((R or S)-(4- chlorophenyl)(1-(2,2,2- trifluoroethyl)piperidin-4-yl)methyl)-2-methyl-3- oxopiperazine-1- carboxamide 446.9 447.4 SFC:AS-H Co-solvent: 25% (IPA + 0.2% DIPEA) peak 1 16B

(2R)-N-((S or R)-(4- chlorophenyl)(1-(2,2,2- trifluoroethyl)piperidin-4-yl)methyl)-2-methyl-3- oxopiperazine-1- carboxamide 446.9 447.4 SFC:AS-H Co-solvent 25% (IPA + 0.2% DIPEA) peak 2 17A

N-((R or S)-(3-chloro-4- flurophenyl)(1-(2,2,2-trifluoroethyl)piperidin- 4-yl)methyl)-3- oxopiperazine-1- carboxamide450.9 451.4 SFC: OD- H Co- solvent; 25% (IPA + 0.2% DIPEA) peak 1 17B

N-((S or R)-(3-chloro-4- fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin- 4-yl)methyl)-3- oxopiperazine-1- carboxamide450.9 451.4 SFC: OD- H Co- solvent: 25% (IPA + 0.2% DIPEA) peak 2

Examples 18A, 18B, 18C and 18D(2R)—N—((R)-(3-chloro-4-fluorophenyl)(1-(R)-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide,(2R)—N—((R)-(3-chloro-4-fluorophenyl)(1-(S)-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide,(2R)—N—((S)-(3-chloro-4-fluorophenyl)(1-(R)-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamideand(2R)—N—((S)-(3-chloro-4-fluorophenyl)(1-(S)-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide

Step 1: tert-butyl 4-(3-chloro-4-fluorobenzoyl)piperidine-1-carboxylateTo a solution of tert-butyl4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (542 mg, 1.990mmol) in THF (8 mL) at 0° C. was added 3-chloro-4-fluorophenylmagnesiumbromide in THF (0.5 M, 7.96 mL, 3.98 mmol). The mixture was stirred at0° C. for 30 minutes, then warmed to RT for 2 hours. The reaction wasthen quenched with saturated aqueous NH₄Cl and extracted with diethylether. The separated organic layer was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound. LRMS m z(M+H): calculated 341.8, observed 342.4.

Step 2: (3-chloro-4-fluorophenyl)(piperidin-4-yl)methanone hydrochlorideTo a solution of tert-butyl4-(3-chloro-4-fluorobenzoyl)piperidine-1-carboxylate (680 mg, 1.989mmol) in CH₂Cl₂ (3 mL) and MeOH (1 mL) was added HCl in 1,4-dioxane (4M, 3 mL, 12.00 mmol). The mixture was stirred at RT for 3 hours and thenconcentrated under reduced pressure to give the title compound. LRMS m/z(M+H): calculated 241.7, observed 242.2.

Step 3:(3-chloro-4-fluorophenyl)(1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methanoneTo a solution of (3-chloro-4-fluorophenyl)(piperidin-4-yl)methanonehydrochloride in DMF (5 mL) were added 1,1,1-trifluoropropan-2-yltrifluoromethanesulfonate (636 mg, 2.58 mmol) and Et₃N (1.108 mL, 7.95mmol). The mixture was heated to 50° C. for 20 hours, then cooled to RT,quenched with H₂O and extracted with ethyl acetate. The separatedorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel, eluting with (0-40% ethyl acetate/hexane)to give the title compound. LRMS m/z (M+H): calculated 337.7, observed338.3.

Step 4:(S)—N—((Z)-(3-chloro-4-fluorophenyl)(1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)-methylene)-2-methylpropane-2-sulfinamideA microwave tube was charged with(3-chloro-4-fluorophenyl)(1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methanone(188 mg, 0.557 mmol), (S)-(−)-2-methyl-2-propane sulfinamide (135 mg,1.113 mmol) and titanium(IV) isopropoxide (1 mL, 3.38 mmol). The mixturewas microwaved at 120° C. for 30 minutes. Then saturated aqueousNaHCO₃(10 mL) and 30 mL ethyl acetate (30 mL). The mixture was stirredat RT for 20 min, and then filtered through a Celite® pad. The separatedorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel, eluting with (0-20% ethyl acetate/hexane)to give the title compound. LRMS m/z (M+H): calculated 440.9, observed441.4.

Step 5:(S)—N-((3-chloro-4-fluorophenyl)(1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide(isomers A and B) To a solution of(S)—N—((Z)-(3-chloro-4-fluorophenyl)(1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methylene)-2-methylpropane-2-sulfinamide(174 mg, 0.395 mmol) in THF (1 mL) and MeOH (500 μL) was added NaBH₄(59.7 mg, 1.578 mmol) at RT. The mixture was stirred at RT for 3 hoursand then partitioned between ethyl acetate and saturated aqueous NaHCO₃.The organic layer was separated and then washed with brine. Theseparated organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting residue was purified bypreparative TLC, eluting with (40% ethyl acetate in hexane) to give thetitle compounds: Isomer A (first eluted fraction): LRMS m/z (M+H):calculated 442.9, observed 443.4; and Isomer B (second eluted fraction):LRMS m/z (M+H): calculated 442.9, observed 443.4.

Step 6:(3-chloro-4-fluorophenyl)(1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methanaminehydrochloride To a solution of(S)—N-((3-chloro-4-fluorophenyl)(1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-2-methylpropane-2-sulfinamide(Isomer A, 48 mg, 0.108 mmol) in CH₂Cl₂ (500 μL) and MeOH (500 μL) wasadded HCl in 1,4-dioxane (4 M, 1 mL, 4.00 mmol). The mixture was stirredat RT for 2 hours and then concentrated under reduced pressure. Theresulting residue was washed with hexane (2×10 mL), filtered to removethe solvent and dried under reduced pressure to give the title compound.LRMS m/z (M+H): calculated 338.8, observed 339.3.

Step 7: Examples 18A and 18B To a solution of(3-chloro-4-fluorophenyl)(1-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methanamineHCl (41.5 mg, 0.111 mmol) in CH₂Cl₂ (2 mL) at 0° C. were added Et₃N(0.092 mL, 0.664 mmol) and triphosgene (32.8 mg, 0.111 mmol). Themixture was stirred at 0° C. for 1 hour and then(R)-3-methylpiperazin-2-one (18.94 mg, 0.166 mmol) was added. Afterstirring at 0° C. for 1 hour, the reaction warmed to RT for 1 hour andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography on silica gel, eluting with (0-4% MeOH/DCM) togive a mixture, which was separated by SFC (OJ-H column, 20% (EtOH+0.2%DIPEA) co-solvent) to give Examples 18A (first eluted fraction) and 18B(second eluted fraction).

Example 18A: LRMS m/z (M+H): calculated 478.9, observed 479.4. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.31 (s, 1H), 7.12 (d, J=6.9 Hz, 2H),6.39 (s, 1H), 5.12 (s, 1H), 4.66 (s, 1H), 4.51 (s, 1H), 4.24 (d, J=13.3Hz, 1H), 3.57-3.46 (m, 1H), 3.31 (d, J=11.4 Hz, 1H), 3.23-3.07 (m, 2H),2.94 (s, 2H), 2.56 (s, 1H), 2.36 (s, 1H), 1.76 (d, J=11.6 Hz, 1H), 1.63(s, 2H), 1.49 (d, J=7.0 Hz, 3H), 1.37 (s, 2H), 1.23 (s, 3H). Example18B: LRMS m/z (M+H): calculated 478.9, observed 479.4. ¹H NMR δ (ppm)(500 MHz, Chloroform-d): 7.30 (s, 1H), 7.12 (d, J=6.9 Hz, 2H), 6.25 (s,1H), 5.01 (s, 1H), 4.66 (s, 1H), 4.47 (s, 1H), 4.24 (d, J=12.9 Hz, 1H),3.52 (t, J=7.8 Hz, 1H), 3.31 (d, J=9.6 Hz, 1H), 3.23-3.08 (m, 2H), 2.99(s, 1H), 2.86 (s, 1H), 2.55 (s, 1H), 2.38 (s, 1H), 1.79 (d, J=12.2 Hz,1H), 1.63 (s, 2H), 1.50 (d, J=7.0 Hz, 3H), 1.36 (s, 2H), 1.24 (s, 3H).

Step 8: Examples 18C and 18D Examples 18C and 18D were preparedaccording to the synthetic procedure for Examples 18A and 18B by usingisomer B from Step 5. Example 18C (first eluted fraction) and Example18D (second eluted fraction) were separated by SFC (OD-H column, 15%(EtOH+0.2% DIPEA) co-solvent). Example 18C: LRMS m/z (M+H): calculated478.9, observed 479.4. ¹H NMR δ (ppm) (500 MHz, Chloroform-d): 7.40 (dd,J=7.0, 2.0 Hz, 1H), 7.19-7.13 (m, 1H), 7.09 (t, J=8.6 Hz, 1H), 6.27 (d,J=3.3 Hz, 1H), 5.38 (d, J=6.5 Hz, 1H), 4.59 (t, J=7.9 Hz, 1H), 4.52 (d,J=6.9 Hz, 1H), 4.29 (d, J=12.5 Hz, 1H), 3.45 (td, J=11.6, 4.2 Hz, 1H),3.33-3.25 (m, 1H), 3.21-3.09 (m, 2H), 2.95 (d, J=10.0 Hz, 1H), 2.89 (d,J=9.2 Hz, 1H), 2.58 (t, J=10.7 Hz, 1H), 2.33 (s, 1H), 1.83 (d, J=12.3Hz, 1H), 1.66 (d, J=8.9 Hz, 2H), 1.54 (d, J=7.0 Hz, 3H), 1.40-1.30 (m,2H), 1.22 (d, J=6.2 Hz, 3H).

Example D: LRMS m/z (M+H): calculated 478.9, observed 479.4. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.39 (d, J=6.6 Hz, 1H), 7.19-7.13 (m,1H), 7.10 (t, J=8.6 Hz, 1H), 6.27 (s, 1H), 5.34 (d, J=16.6 Hz, 1H), 4.60(d, J=7.7 Hz, 1H), 4.52 (s, 1H), 4.29 (d, J=12.8 Hz, 1H), 3.46 (dt,J=11.4, 5.8 Hz, 1H), 3.29 (d, J=12.1 Hz, 1H), 3.22-3.10 (m, 2H), 3.00(s, 1H), 2.84 (s, 1H), 2.54 (s, 1H), 2.39 (t, J=10.4 Hz, 1H), 1.86 (d,J=13.1 Hz, 1H), 1.73-1.57 (m, 2H), 1.55 (d, J=7.0 Hz, 3H), 1.28 (t,J=7.1 Hz, 2H), 1.24 (d, J=6.1 Hz, 3H).

Examples 19A, 19B, 19C and 19D(2R)—N—((R)-(3-chloro-4-fluorophenyl)(trans-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide,(2R)—N—((S)-(3-chloro-4-fluorophenyl)(trans-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide,(2R)—N—((R)-(3-chloro-4-fluorophenyl)(cis-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamideand(2R)—N—((S)-(3-chloro-4-fluorophenyl)(cis-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide

Step 1:(3-chloro-4-fluorophenyl)(1,1-difluorospiro[2.5]octan-6-yl)methanone Toa solution of 1,1-difluorospiro[2.5]octane-6-carboxylic acid (318 mg,1.672 mmol) in CH₂Cl₂ (4 mL) at 0° C. was added (COCl)₂ in DCM (2 M,1.672 mL, 3.34 mmol) and one drop of DMF. The mixture was warmed to RTand stirred for 4 hours, followed by heating to 40° C. for 30 minutes.The mixture was then concentrated under reduced pressure. The resultingresidue was redissolved in THF (4 mL) to prepare solution A. In aseparate reaction flask, copper(I) cyanide (374 mg, 4.18 mmol) wassuspended in THF (4 mL) and cooled to 0° C., followed by the addition of(3-chloro-4-fluorophenyl) magnesium bromide in THF (0.5 M, 6.69 mL, 3.34mmol). The mixture was stirred at 0° C. for 1 hour, then added tosolution A and stirred at 0° C. for 2 hours, then warmed to RT for 2hours. The reaction mixture was partitioned between ethyl acetate andsaturated aqueous NH₄Cl, and filtered thorough a Celite® pad. Theseparated organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give the title compound. LRMS m z (M+H):calculated 302.7, observed 302.9.

Step 2:(3-chloro-4-fluorophenyl)(1,1-difluorospiro[2.5]octan-6-yl)methanaminehydrochloride A microwave tube was charged with(3-chloro-4-fluorophenyl)(1,1-difluorospiro[2.5]octan-6-yl)methanone(506 mg, 1.672 mmol), ammonium acetate (1031 mg, 13.37 mmol) and ethanol(10 mL). The mixture was microwaved at 125° C. for 15 min and cooled toRT, followed by addition of sodium cyanoborohydride (126 mg, 2.006mmol). The reaction was microwaved at 125° C. for 15 min, then cooled toRT and quenched with 30 mL of 10% aqueous K₂CO₃ and extracted with ethylacetate (2×30 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas treated with HCl (2 M, 2 mL) in diethy ether and the resulting solidwas filtered off to give the title compound.

LRMS m/z (M+H): calculated 303.7, observed 304.0.

Step 3: examples 19A, 19B, 19C and 19D To a suspension of(3-chloro-4-fluorophenyl)(1,1-difluorospiro[2.5]octan-6-yl)methanaminehydrochloride (160 mg, 0.527 mmol) in CH₂Cl₂ (3 mL) at 0° C. were addedtriphosgene (156 mg, 0.527 mmol) and Et₃N (0.367 mL, 2.63 mmol). Themixture was stirred at 0° C. for 1 hour, then(R)-3-methylpiperazin-2-one (90 mg, 0.790 mmol) was added. The reactionwas stirred at 0° C. for 1 hour, then warmed to RT for 1 hour andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography on silica gel, eluting with (0-4% MeOH/DCM) togive a mixture, which was separated by SFC (AD-H column, 20% (EtOH+0.2%DIPEA) co-solvent) to give Examples 19A (first eluted fraction), 19B(second eluted fraction), 19C (third eluted fraction) and 19D (fourtheluted fraction).

Example 19A: LRMS m/z (M+H): calculated 443.9, observed 444.3. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.31 (d, J=6.8 Hz, 1H), 7.15-7.11 (m,2H), 6.19 (d, J=15.9 Hz, 1H), 4.92 (s, 1H), 4.64 (t, J=8.2 Hz, 1H), 4.43(s, 1H), 4.22 (d, J=12.7 Hz, 1H), 3.51 (td, J=11.5, 4.2 Hz, 1H),3.37-3.29 (m, 1H), 3.14 (ddd, J=14.4, 11.2, 3.6 Hz, 1H), 2.02-1.93 (m,1H), 1.72-1.60 (m, 4H), 1.48 (dd, J=7.0, 4.2 Hz, 3H), 1.29-1.18 (m, 3H),1.07 (dt, J=20.4, 7.7 Hz, 3H).

Example 19B: LRMS m/z (M+H): calculated 443.9, observed 444.3. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.31 (d, J=6.5 Hz, 1H), 7.16-7.11 (m,2H), 6.02 (s, 1H), 4.81 (s, 1H), 4.66 (t, J=8.4 Hz, 1H), 4.39 (d, J=6.5Hz, 1H), 4.22 (d, J=14.6 Hz, 1H), 3.56-3.47 (m, 1H), 3.36-3.29 (m, 1H),3.15 (ddd, J=14.5, 11.2, 3.7 Hz, 1H), 1.98 (d, J=12.6 Hz, 1H), 1.73-1.59(m, 4H), 1.48 (d, J=7.1 Hz, 3H), 1.29-1.21 (m, 4H), 0.99 (td, J=7.9, 3.8Hz, 2H).

Example 19C: LRMS m/z (M+H): calculated 443.9, observed 444.3. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.34 (d, J=6.9 Hz, 1H), 7.18-7.05 (m,2H), 5.99 (s, 1H), 4.96 (s, 1H), 4.68 (t, J=8.0 Hz, 1H), 4.41 (d, J=6.8Hz, 1H), 4.28 (d, J=12.9 Hz, 1H), 3.47 (td, J=11.6, 4.3 Hz, 1H), 3.30(d, J=11.8 Hz, 1H), 3.16 (ddd, J=14.5, 11.3, 3.7 Hz, 1H), 1.92 (d,J=13.1 Hz, 1H), 1.77-1.58 (m, 4H), 1.56 (d, J=7.1 Hz, 3H), 1.51 (d,J=15.2 Hz, 1H), 1.30-1.08 (m, 3H), 1.06 (t, J=8.6 Hz, 2H).

Example 19D: LRMS m/z (M+H): calculated 443.9, observed 444.3. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.38 (s, 1H), 7.19-7.09 (m, 2H), 6.06 (s,1H), 5.12 (s, 1H), 4.66 (s, 1H), 4.43 (s, 1H), 4.29 (d, J=12.3 Hz, 1H),3.47 (t, J=11.0 Hz, 1H), 3.30 (d, J=11.5 Hz, 1H), 3.16 (t, J=12.1 Hz,1H), 1.97 (d, J=12.6 Hz, 1H), 1.80-1.58 (m, 4H), 1.55 (d, J=6.9 Hz, 3H),1.29-1.20 (m, 4H), 0.99 (t, J=8.6 Hz, 2H).

Examples 20A, 20B, 20C and 20D(R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(20A),(R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(20B),(R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(20C) and(R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(20D)

Step 1:(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclobutyl)methanone Toa solution of 3-(trifluoromethyl)cyclobutane-1-carboxylic acid (1.00 g,5.95 mmol) in CH₂Cl₂ (15 mL) at 0° C. was added (COCl)₂ in DCM (2 M,3.57 mL, 7.14 mmol) and one drop of DMF. The mixture was warmed to RTand stirred at RT for 4 hours. Then the mixture was concentrated underreduced pressure, and the resulting residue was redissolved in THF (6mL) to prepare solution A. In a separate flask,2-chloro-1,3-difluoro-4-iodobenzene (2.449 g, 8.92 mmol) was dissolvedin THF (20 mL), cooled to −20° C., followed by the addition ofisopropylmagnesium chloride-lithium chloride complex in THF (1.3 M, 6.86mL, 8.92 mmol). The mixture was stirred at −20° C. for 2 hours, thenwarmed to 0° C., followed by the addition of copper(I) cyanide (1.066 g,11.90 mmol). The mixture was stirred at 0° C. for 30 minutes, thensolution A was added. The reaction was maintained at 0° C. for 2 hours,warmed to RT for 1 hour, and then partitioned between ethyl acetate andsaturated aqueous NH₄Cl, and filtered thorough a Celite® pad. Theseparated organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give the title compound. LRMS m z (M+H):calculated 298.6, observed 299.1.

Step 2:(R,E)-N-((3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclobutyl)methylene)-2-methylpropane-2-sulfinamideA microwave tube was charged with(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl) cyclobutyl)methanone(1.7 g, 5.69 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (1.035 g, 8.54mmol) and tetraethoxytitanium (10.46 mL, 11.39 mmol). The reactionmixture was microwaved at 105° C. for 1 hour, then cooled to RT andpoured into H₂O (30 mL) and 50 ml ethyl acetate (50 mL). The mixture wasstirred for 10 min, and then filtered through a Celite® pad. Theseparated organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give the title compound. LRMS m/z (M+H):calculated 401.8, observed 402.3.

Step 3:(R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methylpropane-2-sulfinamide(isomer A),(R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methylpropane-2-sulfinamide(isomer B-1),(R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methylpropane-2-sulfinamide(isomer B-2) and(R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoro-methyl)cyclobutyl)methyl)-2-methylpropane-2-sulfinamide(isomer C) To a solution of(R,E)-N-((3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclobutyl)methylene)-2-methylpropane-2-sulfinamide (2.2 g, 5.48 mmol) in THF (10mL) and MeOH (2 mL) at 0° C. was added NaBH₄ (0.207 g, 5.48 mmol). Themixture was stirred at 0° C. for 1 hour, then warmed to RT for 1 hourand partitioned between ethyl acetate and saturated aqueous NaHCO₃. Theseparated organic layer was dried over Na₂SO₄, filtered and concentratedunder reduced pressure. The resulting residue was purified by columnchromatography on silica gel, eluting with (0-40% ethyl acetate/hexane)to give a mixture which was separated by SFC (AD-H column, 10% MeOHco-solvent) to give isomer A (first eluted fraction), isomer B (secondeluted fraction) and isomer C (third eluted fraction). Isomer B wasfurther separated by SFC (IF-H column, 30% EtOH with 0.25% DIPEAco-solvent) to give isomer B-1 (first eluted fraction) and isomer B-2(second eluted fraction).

Step 4:(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanaminehydrochloride A solution of(R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)-cyclobutyl)-methyl)-2-methylpropane-2-sulfinamide (isomer A, 125 mg, 0.310 mmol) in CH₂Cl₂ (1 mL)was cooled to 0° C., followed by the addition of HCl in 1,4-dioxane (4M, 1 mL, 4 mmol). The mixture was stirred at 0° C. for 2 hours and thenconcentrated under reduced pressure. The resulting residue was washedwith diethyl ether (2×5 mL) and filtered to give the title compound.LRMS m/z (M+H): calculated 299.7, observed 300.2.

Step 5: Example 20A To a suspension of(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoro-methyl)cyclobutyl)methanamine hydrochloride (59 mg, 0.197 mmol) in CH₂Cl₂ (4 mL) at 0° C.was added triphosgene (58.4 mg, 0.197 mmol) and Et₃N (0.082 ml, 0.591mmol). The mixture was stirred at 0° C. for 1 hour, then(R)-3-methylpiperazin-2-one (29.2 mg, 0.256 mmol) was added. Thereaction mixture was stirred at 0° C. for 1 hour, then warmed to RT for1 hour and concentrated under reduced pressure. The resulting residuewas purified by column chromatography on silica gel, eluting with (0-4%MeOH/DCM) to give example 20A. LRMS m/z (M+H): calculated 439.8,observed 440.3. ¹H NMR δ (ppm) (500 MHz, Chloroform-d): 7.22 (q, J=8.0Hz, 1H), 6.97 (t, J=8.2 Hz, 1H), 6.57 (d, J=28.5 Hz, 1H), 5.37-5.21 (m,1H), 5.01 (dd, J=10.7, 8.4 Hz, 1H), 4.56-4.43 (m, 1H), 4.18 (d, J=13.2Hz, 1H), 3.54-3.43 (m, 1H), 3.32 (d, J=11.1 Hz, 1H), 3.20-3.08 (m, 1H),3.00-2.82 (m, 2H), 2.36 (d, J=5.9 Hz, 1H), 2.28-2.17 (m, 1H), 2.09 (q,J=9.9, 6.9 Hz, 1H), 1.97-1.88 (m, 1H), 1.45 (d, J=7.0 Hz, 3H).

Step 6: Examples 20B, 20C and 20D Examples 20B, 20C and 20D wereprepared according to the synthetic procedure for Example 20A by usingthe different isomers obtained in Step 3 as starting materials.

Isomer C gave Example 20B: LRMS m/z (M+H): calculated 439.8, observed440.3. ¹H NMR δ (ppm) (500 MHz, Chloroform-d): 7.22 (q, J=7.5 Hz, 1H),6.97 (t, J=8.3 Hz, 1H), 6.38 (d, J=28.8 Hz, 1H), 5.24 (s, 1H), 5.03 (dd,J=10.9, 8.2 Hz, 1H), 4.44 (d, J=6.6 Hz, 1H), 4.22 (d, J=13.4 Hz, 1H),3.45 (td, J=11.5, 3.7 Hz, 1H), 3.30 (d, J=11.7 Hz, 1H), 3.21-3.11 (m,1H), 3.00-2.84 (m, 2H), 2.37 (dt, J=12.8, 6.5 Hz, 1H), 2.28-2.18 (m,1H), 2.11 (q, J=10.1, 7.1 Hz, 1H), 1.99-1.88 (m, 1H), 1.50 (d, J=7.0 Hz,3H).

Isomer B-1 gave Example 20C: LRMS m/z (M+H): calculated 439.8, observed440.3. ¹H NMR δ (ppm) (500 MHz, Chloroform-d): 7.21 (td, J=8.2, 6.0 Hz,1H), 7.02-6.92 (m, 1H), 6.34 (s, 1H), 4.98 (d, J=8.0 Hz, 1H), 4.94-4.87(m, 1H), 4.39 (q, J=7.1 Hz, 1H), 4.17 (d, J=13.6 Hz, 1H), 3.51 (td,J=11.5, 4.2 Hz, 1H), 3.32 (dq, J=11.7, 3.6 Hz, 1H), 3.15 (ddd, J=14.2,11.1, 3.6 Hz, 1H), 2.83 (dt, J=17.6, 8.8 Hz, 1H), 2.72 (p, J=8.9 Hz,1H), 2.35 (dtd, J=11.9, 8.3, 3.7 Hz, 1H), 2.16-2.06 (m, 1H), 2.06-1.98(m, 1H), 1.93-1.85 (m, 1H), 1.48 (d, J=7.1 Hz, 3H).

Isomer B-2 gave example 20D: LRMS m/z (M+H): calculated 439.8, observed440.3. ¹H NMR δ (ppm) (500 MHz, Chloroform-d): 7.25-7.19 (m, 1H),7.00-6.93 (m, 1H), 6.35 (s, 1H), 5.19 (s, 1H), 4.97 (t, J=8.8 Hz, 1H),4.42 (q, J=6.9 Hz, 1H), 4.24 (d, J=12.8 Hz, 1H), 3.46 (td, J=11.6, 4.2Hz, 1H), 3.34-3.27 (m, 1H), 3.16 (ddd, J=14.3, 11.2, 3.6 Hz, 1H), 2.83(dt, J=17.6, 8.8 Hz, 1H), 2.74 (p, J=9.0 Hz, 1H), 2.31 (dtd, J=11.9,8.2, 3.8 Hz, 1H), 2.16-2.09 (m, 1H), 2.04 (ddd, J=12.0, 8.1, 3.8 Hz,1H), 1.97-1.88 (m, 1H), 1.52 (d, J=7.1 Hz, 3H).

TABLE 3 The following examples were prepared according to the syntheticprocedure for Examples 20A, 20B, 20C and 20D, using the appropriatestarting materials and reagents Calc'd Observed Example Compound Name[M + H]⁺ [M + H]⁺ Conditions 21A

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(trans or cis-3-cyclopropylcyclobutyl) methyl)-2-methyl-3- oxopiperazine-1- carboxamide411.9 412.4 In step 3 SFC: AD-H Co-solvent: 25% EtOH then 10% (IPA +0.2% DIPEA) peak 1 21B

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(cis or trans-3-cyclopropylcyclobutyl) methyl)-2-methyl-3- oxopiperazine-1- carboxamide411.9 412.4 In step 3 SFC: AD-H Co-solvent: 25% EtOH then 10% (IPA +0.2% DIPEA) peak 2 21C

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(trans or cis-3-cyclopropyl-cyclobutyl)- methyl)-2-methyl-3- oxopiperazine-1-carboxamide 411.9 412.4 In step 3 SFC: AD-H Co-solvent: 25% EtOH then10% (IPA + 0.2% DIPEA) peak 3 21D

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(cis or trans-3-cyclopropyl-cyclobutyl)- methyl)-2-methyl-3- oxopiperazine-1-carboxamide 411.9 412.4 In step 3 SFC: AD-H Co-solvent: 25% EtOH then10% (IPA + 0.2% DIPEA) peak 4 22A

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(trans or cis-1,1-difluoro-spiro[2,3]- hexan-5-yl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 433.8 434.4 In step 3 SFC: AD-H Co-solvent; 10% MeOH peak1 22B

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(cis or trans-1,1-difluoro-spiro[2,3]- hexan-5-yl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 433.8 434.4 In step 3 SFC: AD-H Co-solvent: 10% MeOH peak2 22C

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(trans or cis-1,1-difluoro-spiro[2.3]- hexan-5-yl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 433.8 434.4 In step 3 SFC: AD-H Co-solvent: 10% MeOH peak3 22D

(2R)-N-((So or R)-(3- chloro-2,4-difluoro- phenyl)(cis or trans-1,1-difluoro-spiro[2.3]- hexan-5-yl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 433.8 434.4 In step 3 SFC: AD-H Co-solvent: 10% MeOH peak4 23

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(6,6-difluoro-spiro[3.3]heptan-2- yl)methyl)-2-methyl-3- oxopiperazine-1- carboxamide447.8 448.4 In step 3 SFC: AD-H Co-solvent: 20% MeOH peak 1 24A

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(3,3-difluoro-cyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 407.8 408.3In step 5 SFC: OJ-H Co-solvent: 30% EtOH peak 1 24B

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(3,3-difluoro-cyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 407.8 408.3In step 5 SFC: OJ-H Co-solvent: 30% EtOH peak 2 25A

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(3-methylene-cyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 383.8 384.3In step 3 SFC: AD-H Co-solvent; 35% MeOH peak 1 25B

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(3-methylene-scyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 383.8 384.3In step 3 SFC: AD-H Co-solvent: 35% MeOH peak 2

Example 26N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-3-oxopiperazine-1-carboxamide

To a solution of(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanamine hydrochloride (70 mg, 0.208 mmol) in CH₂Cl₂ (3 ml) at 0° C.were added Et₃N (0.116 mL, 0.833 mmol) and triphosgene (61.8 mg, 0.208mmol). The mixture was stirred at 0° C. for 1 hour, and piperazin-2-one(27.1 mg, 0.271 mmol) was added. Then the reaction mixture was stirredat 0° C. for 1 hour, warmed to RT for 1 hour and concentrated underreduced pressure. The resulting residue was purified by columnchromatography on silica gel, eluting with (0-4% MeOH/DCM) to giveExample 26. LRMS m z (M+H): calculated 425.8, observed 426.4. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.22 (q, J=8.1 Hz, 1H), 6.98 (t, J=8.3Hz, 1H), 6.51 (d, J=23.9 Hz, 1H), 5.03 (dd, J=10.8, 7.9 Hz, 1H), 4.08(s, 2H), 3.68 (t, J=5.1 Hz, 2H), 3.43 (s, 2H), 3.04-2.84 (m, 2H), 2.37(q, J=9.7, 6.5 Hz, 1H), 2.28-2.18 (m, 1H), 2.09 (d, J=13.5 Hz, 1H),2.00-1.83 (m, 2H).

Examples 27A and 27B (R orS)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-cyclopropyl-3-oxopiperazine-1-carboxamideand (S orR)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-cyclopropyl-3-oxopiperazine-1-carboxamide

To a solution of(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanamine hydrochloride (95.8 mg, 0.285 mmol) in CH₂Cl₂ (4 mL) at 0°C. were added Et₃N (0.199 mL, 1.425 mmol) and triphosgene (85 mg, 0.285mmol). The mixture was stirred at 0° C. for 1 hour and3-cyclopropylpiperazin-2-one (51.9 mg, 0.371 mmol) was added. Afterstirring at 0° C. for 1 hour, the reaction was warmed to RT for 1 hourand concentrated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel, eluting with (0-4%MeOH/DCM) to give a mixture of isomers, which was further separated bySFC (OD-H column, 30% MeOH co-solvent) to give Examples 27A (firsteluted fraction) and 27B (second eluted fraction).

Example 27A: LRMS m/z (M+H): calculated 465.8, observed 466.4. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.21 (td, J=8.2, 6.0 Hz, 1H), 6.98 (t,J=8.3 Hz, 1H), 6.52 (s, 1H), 5.11 (d, J=8.3 Hz, 1H), 5.03-4.96 (m, 1H),4.15 (d, J=6.8 Hz, 1H), 4.03 (d, J=13.2 Hz, 1H), 3.51-3.43 (m, 1H),3.42-3.30 (m, 2H), 2.94 (dq, J=9.9, 5.1 Hz, 1H), 2.86 (dt, J=16.5, 8.5Hz, 1H), 2.37 (d, J=6.3 Hz, 1H), 2.28-2.17 (m, 1H), 2.11 (s, 1H),1.94-1.84 (m, 1H), 1.27-1.21 (m, 1H), 0.66 (dt, J=9.5, 4.7 Hz, 1H), 0.57(ddt, J=12.9, 8.5, 4.9 Hz, 2H), 0.47 (q, J=7.4, 5.3 Hz, 1H).

Example 27B: LRMS m/z (M+H): calculated 465.8, observed 466.4. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.20 (td, J=8.2, 6.0 Hz, 1H), 7.01-6.92(m, 1H), 6.66 (s, 1H), 5.22 (d, J=8.0 Hz, 1H), 5.04 (dd, J=11.0, 8.0 Hz,1H), 4.18-4.08 (m, 2H), 3.47-3.39 (m, 1H), 3.38-3.31 (m, 2H), 2.95 (ddt,J=14.7, 9.8, 5.0 Hz, 1H), 2.86 (dt, J=16.7, 8.7 Hz, 1H), 2.36 (dt,J=12.8, 6.5 Hz, 1H), 2.29-2.20 (m, 1H), 2.11 (dq, J=13.4, 7.0, 6.2 Hz,1H), 1.99-1.88 (m, 1H), 1.32-1.27 (m, 1H), 0.74-0.67 (m, 1H), 0.61 (ddt,J=21.8, 8.3, 4.3 Hz, 2H), 0.51 (dq, J=10.1, 5.1 Hz, 1H).

Examples 28A and 28B(2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(spiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamideand(2R)—N—((S)(3-chloro-2,4-difluorophenyl)(spiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide

Example 28A: (2R)—N—((R orS)-(3-chloro-2,4-difluorophenyl)(spiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamideTo a 0° C. solution of diethylzinc in hexane (1 M, 2.215 mL, 2.215 mmol)in CH₂Cl₂ (5 mL) was added dropwise TFA (0.171 mL, 2.215 mmol) in CH₂Cl₂(500 μL). The mixture was stirred 1 hour, then diiodomethane (0.179 mL,2.215 mmol) was added. Then after 40 minutes, (2R)—N—((R orS)(3-chloro-2,4-difluorophenyl)(3-methylene-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(Example 25A, 170 mg, 0.443 mmol) in CH₂Cl₂ (1 mL) was added. Thereaction was stirred for 2 hours and then quenched with saturatedaqueous NH₄Cl. The separated organic layer was dried (MgSO₄), filteredand concentrated under reduced pressure. The resulting residue waspurified by column chromatography on silica gel, eluting with (0-3%MeOH/CH₂Cl₂) to give Example 28A. LRMS m/z (M+H): calculated 397.9,observed 398.3. ¹H NMR δ (ppm) (500 MHz, Chloroform-d): 7.21 (q, J=8.1Hz, 1H), 6.95 (t, J=8.4 Hz, 1H), 6.35 (s, 1H), 5.00 (dq, J=15.4, 7.6 Hz,2H), 4.38 (q, J=7.1 Hz, 1H), 4.18 (d, J=15.3 Hz, 1H), 3.56-3.45 (m, 1H),3.35-3.27 (m, 1H), 3.14 (ddd, J=14.2, 11.2, 3.6 Hz, 1H), 2.86 (h, J=7.1Hz, 1H), 2.28-2.15 (m, 1H), 2.08 (d, J=8.3 Hz, 1H), 2.01-1.94 (m, 1H),1.83 (dd, J=11.5, 6.6 Hz, 1H), 1.48 (t, J=7.0 Hz, 3H), 0.53-0.35 (m,4H).

Example 28B: (2R)—N—((S orR)-(3-chloro-2,4-difluorophenyl)(spiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamideExample 28B was prepared according to a the synthetic procedure forExample 28A using Example 25B as the starting material. LRMS m z (M+H):calculated 397.9, observed 398.3. ¹H NMR δ (ppm) (500 MHz,Chloroform-d): 7.25-7.19 (m, 1H), 6.95 (q, J=8.3, 7.6 Hz, 1H), 6.46 (s,1H), 5.07 (d, J=6.5 Hz, 2H), 4.39 (q, J=6.9 Hz, 1H), 4.23 (d, J=13.4 Hz,1H), 3.45 (td, J=11.5, 4.2 Hz, 1H), 3.31-3.26 (m, 1H), 3.19-3.12 (m,1H), 2.87 (d, J=8.1 Hz, 1H), 2.24-2.17 (m, 1H), 2.13-2.07 (m, 1H),2.02-1.94 (m, 1H), 1.87 (dd, J=11.5, 6.7 Hz, 1H), 1.51 (d, J=7.1 Hz,3H), 0.44 (t, J=9.5 Hz, 4H).

Examples 29A and 29B(2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamideand(2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide

Step 1:(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)methanoneTo a solution of 3-(difluoromethyl)cyclobutane-1-carboxylic acid (1.00g, 6.66 mmol) in CH₂Cl₂ (15 mL) at 0° C. was added (COCl)₂ in CH₂Cl₂ (2M, 3.66 mL, 7.33 mmol) and one drop of DMF. The mixture was warmed to RTfor 4 hours and then concentrated under reduced pressure. The resultingresidue was dissolved in THF (6 mL) to prepare solution A. In a separateflask, a solution of 2-chloro-1,3-difluoro-4-iodobenzene (2.74 g, 9.99mmol) in THF (20 mL) was cooled to −20° C., followed by the addition ofisopropyl magnesium chloride-lithium chloride complex in THF (1.3 M,7.69 mL, 9.99 mmol). The resulting mixture was stirred at −20° C. for 2hours, then warmed to 0° C., followed by addition of copper(I) cyanide(1.193 g, 13.32 mmol). The mixture was stirred at 0° C. for 30 minutes,followed by the addition of solution A. The reaction was maintained at0° C. for 2 hours, then warmed to RT for 1 hour, and quenched withsaturated aqueous NH₄Cl (40 mL) and extracted with ethyl acetate (2×30mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby column chromatography on silica gel, eluting with (0-20% ethylacetate/hexane) to give a trans/cis mixture, which was separated by SFC(AD-H column, 10% MeOH co-solvent) to give the title compound (transisomer, second eluted fraction from SFC). LRMS m/z (M+H): calculated280.6, observed 281.3.

Step 2:(R)—N-((E)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)methylene)-2-methylpropane-2-sulfinamide A microwave tube was chargedwith (3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)methanone (180 mg, 0.641 mmol), (R)-2-methyl-2propanesulfinamide (117 mg, 0.962 mmol), tetraethoxytitanium (0.403 mL,1.924 mmol) and toluene (1.5 mL). The mixture was microwaved at 105° C.for 1 hour, and then cooled to RT, followed by the addition of H₂O (20mL) and ethyl acetate (20 mL). The mixture was stirred for 10 minutes,then filtered through a Celite® pad. The separated organic layer wasdried over Na₂SO₄, filtered and concentrated under reduced pressure togive the title compound.

LRMS m/z (M+H): calculated 383.8, observed 384.3.

Step 3:(R)—N-((3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)methyl)-2-methylpropane-2-sulfinamideTo a solution of(R)—N-((E)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)methylene)-2-methylpropane-2-sulfinamide (246 mg, 0.641 mmol) in THF (4mL) and water (200 μL) at −78° C. was added NaBH₄ (72.7 mg, 1.923 mmol).The mixture was stirred at −78° C. for 3 h, then gradually warmed to RTand partitioned between ethyl acetate and saturated aqueous NaHCO₃. Theseparated organic layer was dried over Na₂SO₄, filtered and concentratedunder reduce pressure to give the title compound. LRMS m/z (M+H):calculated 385.8, observed 386.4.

Step 4:(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)methanaminehydrochloride To a solution of(R)—N-((3-chloro-2,4-difluorophenyl)(trans-3-(difluoro-methyl)cyclobutyl)methyl)-2-methylpropane-2-sulfinamide (167 mg, 0.433 mmol) in CH₂Cl₂ (1mL) at 0° C. was added HCl in 1,4-dixoane (4 M, 1 mL, 4.00 mmol). Themixture was stirred at 0° C. for 2 hours and then rconcentrated underreduced pressure. The resulting residue was washed with diethyl ether(2×8 mL), and filtered to give the title compound. LRMS m/z (M+H):calculated 281.7, observed 282.3.

Step 5: Examples 29A and 29B To a solution of(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)methanaminehydrochloride (130 mg, 0.462 mmol) in DCM (5 mL) at 0° C. were addedEt₃N (0.257 mL, 1.846 mmol) and triphosgene (137 mg, 0.462 mmol). Themixture was stirred at 0° C. for 1 hour, then(R)-3-methylpiperazin-2-one (52.7 mg, 0.462 mmol) was added. Thereaction was stirred at 0° C. for 1 hour, then warmed to RT over 1 hour,and concentrated the reaction mixture under reduced pressure. Theresulting residue was purified by column chromatography on silica gel,eluting with (0-4% MeOH/DCM) to give a mixture of isomers which wasfurther separated by SFC (AD-H column, 20% EtOH co-solvent) to giveExamples 29A (first eluted fraction) and 29B (second eluted fraction).

Example 29A: LRMS m/z (M+H): calculated 421.8, observed 422.5. ¹H NMR δ(ppm) (500 MHz, DMSO-d6): 7.20 (d, J=5.6 Hz, 1H), 6.97 (t, J=8.3 Hz,1H), 5.86 (td, J=57.1, 3.7 Hz, 1H), 4.96 (s, 1H), 4.37 (s, 1H),4.20-4.15 (m, 1H), 3.51 (td, J=11.3, 4.0 Hz, 1H), 3.36-3.29 (m, 1H),3.16 (t, J=12.2 Hz, 1H), 2.75 (d, J=40.6 Hz, 2H), 2.28 (d, J=6.0 Hz,1H), 2.19-2.09 (m, 1H), 2.01 (s, 1H), 1.90-1.78 (m, 1H), 1.48 (d, J=7.0Hz, 3H).

Example 29B: LRMS m/z (M+H): calculated 421.8, observed 422.5. ¹H NMR δ(ppm) (500 MHz, DMSO-d6): 7.21 (q, J=7.0 Hz, 1H), 6.97 (t, J=8.3 Hz,1H), 6.24 (s, 1H), 5.86 (td, J=57.1, 3.7 Hz, 1H), 5.05-4.99 (m, 1H),4.39 (s, 1H), 4.22 (d, J=13.4 Hz, 1H), 3.54-3.41 (m, 1H), 3.30 (d, J=9.8Hz, 1H), 3.17 (t, J=10.9 Hz, 1H), 2.87-2.63 (m, 2H), 2.28 (dt, J=12.2,6.0 Hz, 1H), 2.12 (dd, J=17.8, 10.9 Hz, 1H), 2.01 (s, 1H), 1.90-1.81 (m,1H), 1.73 (s, 1H), 1.51 (d, J=7.0 Hz, 3H).

Examples 30A and 30B(2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamideand(2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide

Step 1:N-methoxy-N-methyl-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamideTo a mixture of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylicacid (300 mg, 1.666 mmol) in DCM (12 mL) was added CDI (540 mg, 3.33mmol) under N₂ at 25° C. The mixture was stirred at 25° C. for 1 hourunder N₂, then N,O-dimethylhydroxylamine hydrochloride (244 mg, 2.498mmol) and triethylamine (0.696 mL, 5.00 mmol) were added. The reactionmixture was stirred at 25° C. for 12 hours under N₂, then concentratedunder reduced pressure. The resulting residue was purified by flashsilica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column,eluent of 10-50% ethyl acetate/pet. ether) to give the title compound.¹H NMR (CDCl₃, 400 MHz) δ 3.67 (s, 3H), 3.18 (s, 3H), 2.48-2.07 (m, 6H).

Step 2:(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methanoneTo a mixture of 1-bromo-3-chloro-2,4-difluorobenzene (856 mg, 3.76 mmol)in THF (2 mL) was added isopropyl magnesium chloride (2.90 mL, 3.76mmol, 1.3 M toluene solution) at 0° C. under N₂ over 2 hours. ThenN-methoxy-N-methyl-3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide(280 mg, 1.255 mmol) was added at 0° C. and the reaction stirred at 20°C. under N₂ for 16 hours. The reaction mixture was then dissolved inwater (20 mL) and EtOAc (20 mL). The organic layer was separated and theaqueous layer was back extracted with EtOAc (3×20 mL). The combinedorganic layers were washed with brine (20 mL), dried over anhydrousNa₂SO₄, filtered and the filtrate was evaporated in vacuo. The resultingresidue was purified by Prep-TLC (silica gel, pet. ether/ethylacetate=9/1) to give the title compound. ¹H NMR (500 MHz, CDCl₃) δ7.62-7.67 (m, 1H), 7.07-7.11 (m, 1H), 2.41 (s, 6H).

Step 3:(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methanamineTo a mixture of(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methanone(120 mg, 0.386 mmol) and ammonium acetate (447 mg, 5.79 mmol) in EtOH (2mL) was added sodium cyanoborohydride (36.4 mg, 0.579 mmol) at 25° C.The reaction was stirred under microwave at 130° C. for 10 minutes. Thenthe reaction mixture was concentrated to remove most of the EtOH,treated with 2 N NaOH until pH >10, and extracted with EtOAc (2×20 mL).The combined organic layers were dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure to give the title compound. LRMSm/z (M-16): calculated 311.1, observed 294.9.

Step 4: Examples 30A and 30B A mixture of CDI (62.4 mg, 0.385 mmol) and(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methanamine (100 mg crude) in DCM (2 mL) wasstirred at 20° C. for 1 hour. Then (R)-3-methylpiperazin-2-one (47.6 mg,0.417 mmol) was added. The resulting mixture was stirred at 20° C. for16 hours. Then the mixture was purified by reverse phase HPLC (75:25 to45:55; water (0.1% TFA):MeCN (0.1% TFA)) to give a mixture of isomers,which were further separated by SFC (AD-H column, 5%-40% EtOH with 0.05%DEA co-solvent) to give Examples 30A (first eluted fraction) and 30B(second eluted fraction).

Example 30A: LRMS m/z (M+H): calculated 451.1, observed 452.0. ¹H NMR δ(ppm) (500 MHz, CD₃OD-d4): 7.27-7.42 (m, 1H), 7.11-7.15 (m, 1H),6.66-6.68 (m, 1H), 5.34-5.36 (m, 1H), 4.65 (d, J=7.0 Hz, 1H), 3.94-4.14(m, 1H), 3.20-3.42 (m, 3H), 1.89 (s, 6H), 1.41 (d, J=7.0 Hz, 3H).

Example 30B: LRMS m/z (M+H): calculated 451.1, observed 452.0. ¹H NMR δ(ppm) (500 MHz, CD₃OD-d4): 7.24-7.41 (m, 1H), 7.14 (t, J=8.4 Hz, 1H),5.35 (s, 1H), 4.42-4.69 (m, 1H), 3.90-4.13 (m, 1H), 3.34-3.43 (m, 1H),3.24-3.30 (m, 2H), 1.90 (s, 6H), 1.41 (d, J=7.0 Hz, 3H).

TABLE 4 The following examples were prepared according to the syntheticprocedure for Examples 30A and 30B, using the appropriate startingmaterials and reagents Calc'd Observed Example Compound Name [M + H]⁺[M + H]⁺ Conditions 31A

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(3,3-dimethyl-cyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 399.2 400.2SFC: AD-H Co-solvent: 20% EtOH with 0.1% NH₃H₂O peak 1 31B

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(3,3-dimethyl-cyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 399.2 400.2SFC: AD-H Co-solvent: 20% EtOH with 0.1% NH₃H₂O peak 2 32A

N-((R or S)-(3-chloro- 2,4-difluorophenyl)(3,3- dimethylcyclobutyl)meth-yl)-3-oxopiperazine-1- carboxamide 385.1 386.1 SFC: AD-H Co-solvent: 20%EtOH with 0.1% NH₃H₂O peak 1 32B

N-((S or R)-(3-chloro- 2,4-difluorophenyl)(3,3- dimethylcyclobutyl)meth-yl)-3-oxopiperazine-1- carboxamide 385.1 386.1 SFC: AD-H Co-solvent: 20%EtOH with 0.1% NH₃H₂O peak 2 33A

(2R)-N-((R or S)-(3,3- dimethylcyclobutyl)(6- (trifluoromethyl)pyridin-3-yl)methyl)-2-methyl- 3-oxopiperazine-1- carboxamide 398.2 399.2 SFC:AD-H Co-solvent: 30% EtOH with 0.1% NH₃H₂O peak 1 33B

(2R)-N-((S or R)-(3,3- dimethylcyclobutyl)(6- (trifluoromethyl)pyridin-3-yl)methyl)-2-methyl- 3-oxopiperazine-1- carboxamide 398.2 399.2 SFC:AD-H Co-solvent: 30% EtOH with 0.1% NH₃H₂O peak 2 34A

N-((R or S)-(3-chloro-4- fluorophenyl)(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)methyl)-3- oxopiperazine-1- carboxamide 419.1 420.2SFC: OJ-3 Co-solvent: 5%-40% EtOH with 0.05% DEA peak 1 34B

N-((S or R)-(3-chloro-4- fluorophenyl)(3- (trifluoromethyl)bicyclo[1.1.1]pentan-1- yl)methyl)-3- oxopiperazine-1- carboxamide 419.1 420.2SFC: OJ-3 Co-solvent: 5%-40% EtOH with 0.05% DEA peak 2 35A

(2R)-N-((R or S)-(3- chloro-4-fluoro- phenyl)(3-(trifluoro-methyl)bicyclo[1.1.1]pen- tan-1-yl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 433.1 434.1 SFC: AD-3 Co-solvent: 5%-40% EtOH with 0.05%DEA peak 1 35B

(2R)-N-((S or R)-(3- chloro-4-fluoro- phenyl)(3-(trifluoro-methyl)bicyclo[1.1.1]pen- tan-1-yl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 433.1 434.1 SFC: AD-3 Co-solvent: 5%-40% EtOH with 0.05%DEA peak 2

Examples 36A, 36B, 36C and 36D(2R)—N—((R)-(4-fluoro-3-methylphenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide,(2R)—N—((S)-(4-fluoro-3-methylphenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide,(2R)—N—((R)-(4-fluoro-3-methylphenyl)(cis-4-(trifluoromethyl)cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamideand(2R)—N—((S)-(4-fluoro-3-methylphenyl)(cis-4-(trifluoromethyl)cyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide

Step 1: N-methoxy-N-methyl-4-(trifluoromethyl)cyclohexane-1-carboxamideTo a mixture of 4-(trifluoromethyl)cyclohexane-1-carboxylic acid 1 (4 g,20.39 mmol) and HATU (11.63 g, 30.6 mmol) in DMF (40 mL) was addedN,O-dimethylhydroxylamine hydrochloride (2.98 g, 30.6 mmol) at 0° C. Theresulting mixture was stirred at 20° C. for 2 hours. Then water (300 mL)was added and the mixture was extracted with ethyl acetate (3×20 mL).The combined organic layers were washed with brine (100 mL), dried overNa₂SO₄, and filtered. The filtrate was evaporated under reducedpressure, and the resulting crude product was purified by flash silicagel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluentof 13% petroleum ether/ethyl acetate) to give the title compound. LRMSm/z (M+H): calculated 339.1, observed 240.1.

Step 2:(4-fluoro-3-methylphenyl)(4-(trifluoromethyl)cyclohexyl)methanone To amixture ofN-methoxy-N-methyl-4-(trifluoromethyl)cyclohexane-1-carboxamide (500 mg,2.090 mmol) in THF (3 mL) was added (4-fluoro-3-methylphenyl) magnesiumbromide (13.79 ml, 6.90 mmol) at 0° C. The resulting mixture was stirredat 20° C. for 18 hours. Then water (15 mL) was added and the mixture wasextracted with ethyl acetate (2×8 mL). The combined organic layers werewashed with brine (15 mL), dried over Na₂SO₄, filtered and the filtratewas evaporated under reduced pressure. The resulting crude product waspurified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®Silica Flash Column, Eluent of 4% petroleum ether/ethyl acetate) to givethe title compound. LRMS m/z (M+H): calculated 288.1, observed 289.1.

Step 3:(4-fluoro-3-methylphenyl)(4-(trifluoromethyl)cyclohexyl)methanamineNH₄OAc (802 mg, 10.41 mmol) and NaBH₃CN (65.4 mg, 1.041 mmol) were addedto a solution of(4-fluoro-3-methylphenyl)(4-(trifluoromethyl)cyclohexyl)methanone (200mg, 0.694 mmol) in EtOH (4 mL) in a microwave vial. The reaction mixturewas stirred and heated at 130° C. for 15 min in a microwave reactor.Then the reaction mixture was concentrated to remove most of the EtOH,treated with 2 N NaOH until pH >10, and extracted with ethyl acetate(2×20 mL). The combined organic layers were dried over Na₂SO₄, filtered,and concentrated under reduced pressure to give the title compound. LRMSm/z (M+H): calculated 289.1, observed 290.1.

Step 4: Examples 36A, 36B, 36C and 36D A mixture of(4-fluoro-3-methylphenyl)(4-(trifluoromethyl)cyclohexyl)methanamine (150mg crude), CDI (168 mg, 1.037 mmol) and DIEA (0.272 mL, 1.555 mmol) inDMF (1 mL) was stirred at 20° C. for 1 hour, followed by the addition of(R)-3-methylpiperazin-2-one (71.0 mg, 0.622 mmol) in DMF (0.5 mL). Theresulting mixture was stirred at 20° C. for 1 hour, and then purified byreverse phase HPLC (53:47 to 33:67; water (0.1% TFA):MeCN (0.1% TFA)),followed by lyophilization to give a mixture of isomers which wasseparated by SFC (OD-H column, 40% EtOH co-solvent) to give Examples 36A(first eluted fraction), 36B (second eluted fraction), 36C (thirdfraction) and 36D (fourth eluted fraction).

Examples 36A: LRMS m/z (M+H): calculated 429.2, observed 430.3. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.89 (br s, 1H), 7.16-7.18 (m, 1H),7.09-7.15 (m, 1H), 6.99-7.06 (m, 1H), 6.77 (d, J=8.4 Hz, 1H), 4.46 (q,J=7.2 Hz, 1H), 4.31 (t, J=9.6 Hz, 1H), 3.88-3.95 (m, 1H), 2.93-3.15 (m,3H), 2.19 (m, 4H), 2.00-2.05 (m, 1H), 1.89-1.93 (m, 1H), 1.70-1.76 (m,1H), 1.59-1.63 (m, 1H), 0.82-1.26 (m, 8H).

Examples 36B: LRMS m/z (M+H): calculated 429.2, observed 430.3. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.19-7.24 (m, 1H), 7.18 (t, J=6.5 Hz,1H), 6.99 (t, J=9.0 Hz, 1H), 4.83-4.89 (m, 2H), 4.56 (q, J=7.0 Hz, 1H),4.01-4.61 (m, 1H), 3.17-3.32 (m, 3H), 2.28 (s, 3H), 2.19-2.23 (m, 1H),2.10 (td, J=4.5, 11.5 Hz, 1H), 1.88-1.97 (m, 1H), 1.72-1.81 (m, 2H),1.64-1.72 (m, 1H), 1.55-1.64 (m, 2H), 1.42 (d, J=7.0 Hz, 3H), 1.30-1.40(m, 1H), 1.26 (dd, J=4.5, 13.5 Hz, 1H).

Example 36C: LRMS m/z (M+H): calculated 429.2, observed 430.3. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.19-7.24 (m, 1H), 7.16-7.19 (m, 1H),7.00 (t, J=9.0 Hz, 1H), 4.84-4.89 (m, 2H), 4.54 (q, J=7.0 Hz, 1H),3.99-4.08 (m, 1H), 3.28-3.31 (m, 1H), 3.16-3.27 (m, 2H), 2.28 (s, 3H),2.19-2.22 (m, 1H), 2.11 (m, 1H), 1.88-1.96 (m, 1H), 1.71-1.81 (m, 2H),1.63-1.70 (m, 1H), 1.55-1.63 (m, 2H), 1.35 (d, J=7.0 Hz, 4H).

Example 36D: LRMS m/z (M+H): calculated 429.2, observed 430.3. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.05 (d, J=7.5 Hz, 1H), 6.99-7.02 (m,1H), 6.86 (t, J=9.0 Hz, 1H), 4.43 (q, J=7.0 Hz, 1H), 4.29 (d, J=10.0 Hz,1H), 3.88-3.96 (m, 1H), 3.16-3.21 (m, 1H), 3.05-3.16 (m, 2H), 2.15 (s,3H), 2.04-2.08 (m, 1H), 1.93-2.03 (m, 1H), 1.86-1.93 (m, 1H), 1.72-1.78(m, 1H), 1.56-1.66 (m, 1H), 1.25 (d, J=7.0 Hz, 5H), 0.93-1.14 (m, 2H),0.79-0.84 (m, 1H)

TABLE 5 The following examples were prepared according to the syntheticprocedure for Examples 36A, 36B, 36C and 36D, using the appropriatestarting materials and reagents Calc'd Observed Example Compound Name[M + H]⁺ [M + H]⁺ Conditions 37A

(2R)-N-((R or S)-(4- chloro-3-(difluoro- methyl)phenyl)(cis-4-(trifluoromethyl) cyclohexyl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 481.2 482.2 SFC: OD-H Co-solvent: 40% EtOH with 0.05% DEApeak 1 37B

(2R)-N-((R or S)-(4- chloro-3-(difluoro- methyl)phenyl)(trans-4-(trifluoromethyl) cyclohexyl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 481.2 482.2 SFC: OD-H Co-solvent: 40% EtOH with 0.05% DEApeak 2 37C

(2R)-N-((S or R)-(4- chloro-3-(difluoro- methyl)phenyl)(cis-4-(trifluoromethyl) cyclohexyl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 481.2 482.2 SFC: OD-H Co-solvent: 40% EtOH with 0.05% DEApeak 3 37D

(2R)-N-((S or R)-(4- chloro-3-(difluoro- methyl)phenyl)(trans-4-(trifluoromethyl) cyclohexyl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 481.2 482.2 SFC: OD-H Co-solvent: 40% EtOH with 0.05% DEApeak 4 38A

(2R)-N-((R or S)-(3- chloro-4-fluoro-phenyl)- (trans-3-(difluoro-methoxy)cyclobutyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide419.1 420.1 SFC: OJ-3 Co-solvent: 5%-40% EtOH with 0.05% DEA peak 1 38B

(2R)-N-((R or S)-(3- chloro-4-fluorophenyl) (cis-3-(difluoromethoxy)cyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 419.1 420.1SFC: OJ-3 Co-solvent: 5%-40% EtOH with 0.05% DEA peak 2 38C

(2R)-N-((S or R)-(3- chloro-4-fluorophenyl) (cis-3-(difluoromethoxy)cyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 419.1 420.1SFC: OJ-3 Co-solvent: 5%-40% EtOH with 0.05 DEA peak 3 38D

(2R)-N-((S or R)-(3- chloro-4-fluorophenyl)- (trans-3-(difluoro-methoxy)cyclobutyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide419.1 420.1 SFC: OJ-3 Co-solvent: 5%-40% EtOH with 0.05% DEA peak 4 39A

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(trans-3-(difluoromethoxy)- cyclobutyl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 437.1 438.1 SFC: OJ-3 Co-solvent: 5%-40% MeOH with 0.05%DEA peak 1 39B

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(cis-3-(difluoro-methoxy)cyclobutyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide437.1 438.1 SFC: OJ-3 Co-solvent: 5%-40% MeOH with 0.05% DEA peak 2 39C

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(cis-3-(difluoro-methoxy)cyclobutyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide437.1 438.1 SFC: OJ-3 Co-solvent: 5%-40% MeOH with 0.05% DEA peak 3 39D

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(trans-3-(difluoro-methoxy)cyclobutyL)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide437.1 438.1 SFC: OJ-3 Co-solvent: 5%-40% MeOH with 0.05% DEA peak 4 40A

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(trans-3-methoxy-cyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 401.1 402.1SFC: OD-H Co-solvent: 5%-40% EtOH with 0.05% DEA peak 1 40B

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(cis-3-methoxy-cyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 401.1 402.1SFC: OD-H Co-solvent: 5%-40% EtOH with 0.05% DEA peak 2 40C

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(cis-3-methoxycyclobutyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide401.1 402.1 SFC: OD-H Co-solvent: 5%-40% EtOH with 0.05% DEA peak 3 40D

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)(trans-3-methoxycyclobutyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide401.1 402.1 SFC: OD-H Co-solvent: 5%-40% EtOH with 0.05% DEA peak 4 41A

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)((R or S)-spiro[2.2]pentan-1- yl)methyl)-2-methyl-3- oxopiperazine-1- carboxamide383.1 384.2 SFC: OJ-H Co-solvent: 30% EtOH with 0.05% DEA peak 1 41B

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)((R or S)-spiro[2.2]pentan-1- yl)methyl)-2-methyl-3- oxopiperazine-1- carboxamide383.1 384.2 SFC: OJ-H Co-solvent: 30% EtOH with 0.05% DEA peak 2 41C

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)(S or R)-spiro[2.2]pentan-1- yl)methyl)-2-methyl-3- oxopiperazine-1- carboxamide383.1 384.2 SFC: OJ-H Co-solvent: 30% EtOH with 0.05% DEA peak 3 41D

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)((S or R)-spiro[2.2]pentan-1- yl)methyl)-2-methyl-3- oxopiperazine-1- carboxamide383.1 384.2 SFC: OJ-H Co-solvent: 30% EtOH with 0.05% DEA peak 4 42A

(2R)-N-((R or S)-(3- choro-2,4-difluoro- phenyl)((R or S)-3,3-difluorocyclopentyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide421.1 422.1 SFC: OJ-H Co-solvent: 30% (MeOH + 0.1% NH₃H₂O) peak 1 42B

(2R)-N-((R or S)-(3- chloro-2,4-difluoro- phenyl)((S or R)-3,3-difluorocyclopentyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide421.1 422.1 SFC: OJ-H Co-solvent: 30% (MeOH + 0.1% NH₃H₂O) peak 2 42C

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)((R or S)-(3,3-difluorocyclopentyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide421.1 422.1 SFC: OJ-H Co-solvent: 30% (MeOH + 0.1% NH₃H₂O) peak 3 42D

(2R)-N-((S or R)-(3- chloro-2,4-difluoro- phenyl)((S or R)-3,3-difluorocyclopentyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide421.1 422.1 SFC: OJ-H Co-solvent: 30% (MeOH + 0.1% NH₃H₂O) Peak 4 43A

(2R)-N-((R or S)-(3- chloro-4-fluorophenyl)- (trans-3-(trifluoro-methyl)-cyclobutyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide421.1 422.0 SFC: OJ-3 Co-solvent: 5%-40% EtOH with 0.05% DEA peak 1 43B

(2R)-N-((R or S)-(3- chloro-4-fluorophenyl)- (cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 421.1 422.0SFC: OJ-3 Co-solvent: 5%-40% EtOH with 0.05% DEA peak 2 43C

(2R)-N-((S or R)-(3- chloro-4-fluorophenyl)- (trans-3-(trifluoro-methyl)-cyclobutyl)- methyl)-2-methyl-3- oxopiperazine-1- carboxamide421.1 422.0 SFC: OJ-3 Co-solvent: 5%-40% EtOH with 0.05% DEA peak 3 2ndSFC: AS-3 Co- solvent: 5%-40% EtOH with 0.05% DEA Peak 1 43D

(2R)-N-((S or R)-(3- chloro-4-fluorophenyl)- (cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2- methyl-3-oxopiperazine- 1-carboxamide 421.1 422.0SFC: OJ-3 Co-solvent: 5%-40% EtOH with 0.05% DEA peak 3 2nd SFC: AS-3Co- solvent: 5%-40% EtOH with 0.05% DEA Peak 2

Examples 44A, 44B, 44C and 44D (2R)—N—((R orS)-(3-chloro-4-fluorophenyl)(cis-3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(44A), (2R)—N—((S orR)-(3-chloro-4-fluorophenyl)(cis-3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(44B), (2R)—N—((R orS)-(3-chloro-4-fluorophenyl)(trans-3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(44C) and (2R)—N—((S orR)-(3-chloro-4-fluorophenyl)(trans-3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(44D)

Step 1: benzyl 3-(2,2,2-trifluoroethoxy)cyclobutane-1-carboxylate To asuspension of NaH (0.389 g, 9.72 mmol) in THF (10 mL) was added benzyl3-hydroxycyclobutane-1-carboxylate (1.67 g, 8.10 mmol) at 0° C. for 10minutes. Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.231 mL,8.91 mmol) was added and the mixture was stirred at 20° C. for 16 hours.The reaction was quenched with saturated aqueous NH₄Cl and extractedwith ethyl acetate (3×10 mL). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered and evaporated underreduced pressure. The resulting residue was purified by Prep-TLC (silicagel, ethyl acetate/pet. ether=1/10, v/v) to give the title compound. ¹HNMR (500 MHz, CDCl₃) δ 7.35-7.38 (m, 5H), 5.14-5.16 (m, 2H), 4.34 (q,J=6.5 Hz, 1H), 3.70-3.78 (m, 2H), 3.06-3.14 (m, 1H), 2.51-2.63 (m, 2H),2.29-2.38 (m, 2H).

Step 2: 3-(2,2,2-trifluoroethoxy)cyclobutane-1-carboxylic acid To asolution of benzyl 3-(2,2,2-trifluoroethoxy)cyclobutane-1-carboxylate(550 mg, 1.908 mmol) in MeOH (10 mL) was added Pd/C (203 mg) under a N₂atmosphere. The reaction mixture was degassed and backfilled with H₂(three times), and the reaction was stirred under H₂ (15 psi) at 20° C.for 12 hours. Then the catalyst was filtered off and the filtrate wasconcentrated under reduced pressure to give the title compound. ¹H NMR(500 MHz, CDCl₃) δ 10.05 (br s, 1H), 4.35 (q, J=6.5 Hz, 1H), 3.66-3.85(m, 2H), 3.01-3.17 (m, 1H), 2.56-2.64 (m, 2H), 2.31-2.45 (m, 2H).

Step 3:N-methoxy-N-methyl-3-(2,2,2-trifluoroethoxy)cyclobutane-1-carboxamide Toa solution of 3-(2,2,2-trifluoroethoxy)cyclobutane-1-carboxylic acid(370 mg, 1.867 mmol) in DCM (5 mL) was added CDI (303 mg, 1.867 mmol) at20° C. The mixture was stirred for 1 hour, then TEA (0.521 mL, 3.73mmol) and N,O-dimethylhydroxylamine hydrochloride (182 mg, 1.867 mmol)were added. The reaction mixture was stirred at 20° C. for another 12hours, followed by the addition of water (10 mL). The reaction mixturewas extracted with DCM (3×5 mL). The combined organic layers were driedover Na₂SO₄, filtered and the filtrate was evaporated under reducedpressure to give the title compound. LRMS m/z (M-16): calculated 241.1,observed 242.1.

Step 4:(3-chloro-4-fluorophenyl)(3-(2,2,2-trifluoroethoxy)cyclobutyl)methanoneTo a solution of 4-bromo-2-chloro-1-fluorobenzene in THF (2 mL) wasadded isopropylmagnesium chloride in THF (2 M, 1.741 mL, 3.48 mmol) at0° C. The reaction mixture was stirred at 20° C. for 1 hour, followed bythe addition of a mixture ofN-methoxy-N-methyl-3-(2,2,2-trifluoroethoxy)-cyclobutane-1-carboxamide(420 mg crude) in THF (1 mL). The reaction was stirred at 20° C. for 2hours, then quenched with saturated aqueous NH₄Cl (5 mL) and extractedwith EtOAc (3×5 mL). The combined organic layers were dried by Na₂SO₄,filtered and the solvent was evaporated under reduced pressure. Theresulting residue was purified by flash silica gel chromatography(ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 4% ethylacetate/pet. ether) to give the title compound. ¹H NMR (400 MHz, CD₃OD)δ 8.02-8.08 (m, 1H), 7.88-7.96 (m, 1H), 7.37 (t, J=8.8 Hz, 1H),4.09-4.24 (m, 1H), 3.96-4.09 (m, 1H), 3.86 (q, J=9.2 Hz, 2H), 2.56-2.64(m, 2H), 2.37-2.48 (m, 2H).

Step 5:(3-chloro-4-fluorophenyl)(3-(2,2,2-trifluoroethoxy)cyclobutyl)methanamineTo a mixture of(3-chloro-4-fluorophenyl)(3-(2,2,2-trifluoroethoxy)cyclobutyl)methanone(250 mg, 0.805 mmol), NH₄OAc (930 mg, 12.07 mmol) in EtOH (3 mL) wasadded NaBH₃CN (76 mg, 1.207 mmol) at 20° C. The mixture was stirredunder microwave (Biotage Initiator) at 130° C. for 10 minutes. Then thereaction mixture was concentrated to remove most of the EtOH, treatedwith 2 N NaOH until pH >12, and extracted with EtOAc (3×5 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, and thefiltrate was concentrated under reduced pressure to give the titlecompound. LRMS m/z (M+H): calculated 311.1, observed 312.0.

Step 6:(2R)—N-((3-chloro-4-fluorophenyl)(cis-3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(isomer A) and(2R)—N-((3-chloro-4-fluorophenyl)(trans-3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(isomer B) A mixture of CDI (260 mg, 1.604 mmol) and(3-chloro-4-fluorophenyl)(3-(2,2,2-trifluoroethoxy)cyclobutyl)methanamine(250 mg crude) in DMF (3 mL) was stirred at 20° C. for 1 hour. Then(R)-3-methylpiperazin-2-one (101 mg, 0.882 mmol) was added. Theresulting mixture was stirred at 20° C. for 2 hours. Then the solid wasfiltered off and the filtrate was purified by reverse phase HPLC (58:42to 28:72; water (0.1% TFA):MeCN (0.1% TFA)) to give two isomers: Firsteluted isomer,(2R)—N-((3-chloro-4-fluorophenyl)(cis-3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide (isomer A).

LRMS m/z (M+H): calculated 451.1, observed 452.2. Second eluted isomer,(2R)—N-((3-chloro-4-fluorophenyl)(trans-3-(2,2,2-trifluoroethoxy)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide (isomer B).LRMS m/z (M+H): calculated 451.1, observed 452.2.

Step 7: Examples 44A, 44B, 44C and 44D Isomer A (150 mg, 0.332 mmol) wasresolved by SFC (AS-H column, 30% (EtOH+0.1% NH₃H₂O) co-solvent) to giveExamples 44A (first eluted fraction) and 44B (second eluted fraction).

Example 44A: LRMS m/z (M+H): calculated 451.1, observed 452.2. ¹H NMR δ(ppm) (500 MHz, CD3OD-d4): 7.40-7.46 (m, 1H), 7.23-7.31 (m, 1H), 7.17(t, J=8.5 Hz, 1H), 4.62-4.68 (m, 1H), 4.48-4.53 (m, 1H), 3.95-4.04 (m,2H), 3.82 (q, J=9.0 Hz, 2H), 3.32-3.38 (m, 1H), 3.17-3.29 (m, 2H),2.48-2.55 (m, 1H), 2.19-2.29 (m, 1H), 2.11-2.18 (m, 1H), 1.76-1.82 (m,1H), 1.63-1.70 (m, 1H), 1.36-1.42 (m, 3H).

Example 44B: LRMS m/z (M+H): calculated 451.1, observed 452.2. ¹H NMR δ(ppm) (500 MHz, CD3OD-d4): 7.40-7.46 (m, 1H), 7.23-7.31 (m, 1H), 7.17(t, J=8.5 Hz, 1H), 4.62-4.68 (m, 1H), 4.56 (q, J=7.2 Hz, 1H), 4.01-4.07(m, 1H), 3.96-4.01 (m, 1H), 3.82 (q, J=9.0 Hz, 2H), 3.32-3.36 (m, 1H),3.17-3.27 (m, 2H), 2.48-2.55 (m, 1H), 2.20-2.27 (m, 1H), 2.09-2.19 (m,1H), 1.76-1.83 (m, 1H), 1.65-1.72 (m, 1H), 1.37-1.43 (m, 3H).

Isomer B (100 mg, 0.221 mmol) was resolved by SFC (OJ-H column, 20%(EtOH+0.1% NH₃H₂O) co-solvent) to give examples 44C (first elutedfraction) and 44D (second eluted fraction).

Example 44C: LRMS m/z (M+H): calculated 451.1, observed 452.2. ¹H NMR δ(ppm) (500 MHz, CD30D-d4): δ 7.42-7.48 (m, 1H), 7.24-7.62 (m, 1H),7.15-7.20 (m, 1H), 4.64-4.70 (m, 1H), 4.54 (q, J=7.0 Hz, 1H), 4.27 (q,J=6.0 Hz, 1H), 4.00-4.07 (m, 1H), 3.82 (q, J=9.0 Hz, 2H), 3.32-3.35 (m,1H), 3.17-3.26 (m, 2H), 2.66-2.75 (m, 1H), 2.21 (t, J=6.5 Hz, 2H),1.91-2.01 (m, 2H), 1.36-1.42 (m, 3H).

Example 44D: LRMS m/z (M+H): calculated 451.1, observed 452.2. ¹H NMR δ(ppm) (500 MHz, CD3OD-d4): δ 7.41-7.47 (m, 1H), 7.23-7.31 (m, 1H),7.16-7.21 (m, 1H), 4.66-4.72 (m, 1H), 4.48-4.53 (m, 1H), 4.26 (q, J=6.0Hz, 1H), 3.98-4.04 (m, 1H), 3.81 (q, J=9.0 Hz, 2H), 3.32-3.36 (m, 1H),3.15-3.27 (m, 2H), 2.67-2.75 (m, 1H), 2.21 (t, J=6.5 Hz, 2H), 1.90-2.01(m, 2H), 1.34-1.40 (m, 3H).

Examples 45A and 45BN—((R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide andN—((S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide

Step 1: 3-chloro-2-(trifluoromethyl)-6-vinylpyridine To a mixture of3,6-dichloro-2-(trifluoromethyl)pyridine (2 g, 9.26 mmol), potassiumtrifluoro(vinyl)borate (1.861 g, 13.89 mmol) and K₂CO₃ (2.56 g, 18.52mmol) in THF (30 mL) and water (3 mL) was added Pd(dppf)Cl₂ (0.339 g,0.463 mmol) at 20° C. under N₂. The mixture was stirred at 80° C. for 12hours. Then water (3 mL) was added and the mixture was extracted withDCM (3×15 mL). The combined organic layers were dried over Na₂SO₄,filtered and the filtrate was concentrated under vacuum to give thetitle compound. LRMS m z (M+H): calculated 207.5, observed 208.0.

Step 2: 5-chloro-6-(trifluoromethyl)picolinaldehyde A mixture of3-chloro-2-(trifluoromethyl)-6-vinylpyridine (1.922 g, 9.26 mmol), NMO(2.169 g, 18.52 mmol) and OSO₄ (4.63 mL, 0.463 mmol) in THF (10 mL) andwater (5 mL) was stirred at 20° C. for 12 hours. Then NaIO4 (5.94 g,27.8 mmol) was added and the mixture was stirred at 20° C. foradditional 2 hours. Then water (60 mL) was added, and the mixture wasextracted with DCM (3×40 mL). The combined organic layers were driedover Na₂SO₄, filtered and the filtrate was concentrated under vacuum togive the title compound. LRMS m z (M+H): calculated 209.6, observed210.0.

Step 3:(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethyl)cyclohexyl)methanoneTo a solution of 5-chloro-6-(trifluoromethyl)picolinaldehyde (600 mgcrude),4-methyl-N′-(4-(trifluoromethyl)cyclohexylidene)benzenesulfonohydrazide(1915 mg, 5.73 mmol) in dioxane (20 mL) was added Cs₂CO₃ (1866 mg, 5.73mmol) at 15° C. Then the reaction was heated to 100° C. for 12 hours,filtered, and the filtrate was concentrated. The resulting residue waspurified by flash silica gel chromatography (ISCO®; 20 g SepaFlash®Silica Flash Column, eluent of 10% ethyl acetate/pet. ether) to give thetitle compound. ¹H NMR (400 MHz, CDCl3) δ 8.12-8.18 (m, 1H), 7.98-8.04(m, 1H), 4.02 (t, J=3.6 Hz, 1H), 2.06-2.20 (m, 5H), 1.72-1.77 (m, 4H).

Step 4:(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethyl)cyclohexyl)methanamineTo a mixture of(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethyl)cyclohexyl)methanone (130 mg, 0.361 mmol), and NH₄OAc (417.89 mg, 5.42 mmol) inEtOH (2 mL) was added NaBH₃CN (34.07 mg, 0.542 mmol) at 20° C. Thereaction mixture was stirred under microwave (Biotage Initiator) at 130°C. for 10 minutes, then concentrated to remove most of the EtOH, treatedwith 2 N NaOH until pH >12, and extracted with EtOAc (3×5 mL). Thecombined organic layers were dried over Na₂SO₄, filtered, and thefiltrate was concentrated under reduced pressure to give the titlecompound. LRMS m/z (M+H): calculated 360.1, observed 361.1.

Step 5:N-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide A mixture of CDI (90 mg, 0.554mmol) and(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(4-(trifluoromethyl)cyclohexyl)methanamine(100 mg crude) in DMF (1.5 mL) was stirred at 20° C. for 1 hour. Thenpiperazin-2-one (30.5 mg, 0.305 mmol) was added. The reaction mixturewas stirred at 20° C. for 1 hour, then the solid was filtered off andthe filtrate was purified by prep-HPLC (53:47 to 23:67; water (0.1%TFA):MeCN (0.1% TFA)) to give two isomers: First eluted isomer,N-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide (trans-isomers). LRMSm/z (M+H): calculated 486.1, observed 487.2. Second eluted isomer,N-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)(cis-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxo-piperazine-1-carboxamide (cis-isomers). LRMSm/z (M+H): calculated 486.1, observed 487.1.

Step 6: Examples 45A and 45BN-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide (80 mg, 0.164 mmol) wasresolved by Chiral-SFC (Column DAICEL CHIRALPAK IC, 30% (EtOH+0.1%NH₃H₂O) co-solvent) to give examples 45A (first eluted fraction) and 45B(second eluted fraction).

Example 45A: LRMS m/z (M+H): calculated 486.1, observed 487.2. ¹H NMR δ(ppm) (500 MHz, CD3OD-d4): 7.99-8.05 (m, 1H), 7.56-7.62 (m, 1H),4.66-4.72 (m, 1H), 4.05 (s, 2H), 3.57-3.66 (m, 2H), 3.33 (br s, 2H),2.05-2.13 (m, 2H), 1.87-2.02 (m, 3H), 1.28-1.40 (m, 2H), 1.06-1.27 (m,3H).

Example 45B: LRMS m/z (M+H): calculated 486.1, observed 487.2. ¹H NMR δ(ppm) (500 MHz, CD3OD-d4): 7.99-8.05 (m, 1H), 7.56-7.62 (m, 1H),4.66-4.72 (m, 1H), 4.05 (s, 2H), 3.57-3.66 (m, 2H), 3.33 (br s, 2H),2.04-2.14 (m, 2H), 1.87-2.02 (m, 3H), 1.27-1.41 (m, 2H), 1.06-1.26 (m,3H).

TABLE 6 The following Examples were prepared according to the syntheticprocedure for Examples 45A and 45B, using the appropriate startingmaterials and reagents Calc'd Observed Example Compound Name [M + H]⁺[M + H]⁺ Conditions 46A

(2R)-N-((R or S)-(5- chloro-6-(trifluoro- methyl)pyridin-2-yl)(4,4-difluoro- cyclohexyl)methyl)- 2-methyl-3-oxo- piperazine-1-carboxamide 468.1 469.1 SFC: AD-H Co-solvent: 20% (IPA + 0.1% NH₃H₂O)peak 1 46B

(2R)-N-((S or R)-(5- chloro-6-(trifluoro- methyl)pyridin-2-yl)(4,4-difluoro- cyclohexyl)methyl)- 2-methyl-3-oxo- piperazine-1-carboxamide 468.1 469.1 SFC: AD-H Co-solvent; 20% (IPA + 0.1% NH₃H₂O)peak 2

Examples 47A, 47B, 47C and 47D (2R)—N—((R orS)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(47A), (2R)—N—((R orS)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(47B), (2R)—N—((S orR)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(47C) and (2R)—N—((S orR)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(47D)

Step 1: 6-bromo-3-chloro-2-(trifluoromethyl)pyridine To a solution of5-chloro-6-(trifluoromethyl)pyridin-2-amine (2 g, 10.18 mmol) andcopper(II) bromide (3.41 g, 15.26 mmol) in acetonitrile (20 mL) wasadded tert-butyl nitrite (2.099 g, 20.35 mmol) at 0° C. The reactionmixture was stirred at 30° C. for 16 hours, then concentrated underreduced pressure, diluted with water (20 mL), and extracted with DCM(3×10 mL). The combined organic layers were washed with brine (20 mL),dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentratedunder reduced pressure, and the resulting residue was purified by MPLC(ISCO®; 12 g SepaFlash® Silica Flash Column, eluent of 0˜8% Pet.ether/EtOAc) to give the title compound. ¹H NMR (500 MHz, CDCl3) δ7.69-7.76 (m, 1H), 7.61-7.67 (m, 1H).

Step 2:(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(3-(trifluoromethyl)cyclobutyl)methanoneTo a solution of 6-bromo-3-chloro-2-(trifluoromethyl)pyridine (555 mg,2.131 mmol) in toluene (6 mL) under N₂ was added butyllithium in THF(2.5 M, 0.796 mL, 1.989 mmol) at −70° C. The mixture was stirred at −70°C. for 1 hour, then N-methoxy-N-methyl-3-(trifluoromethyl)cyclobutanecarboxamide (300 mg, 1.421 mmol) in toluene (3 mL) was added.The reaction was warmed to 0° C., stirred for 1 hour and quenched withwater (20 mL), extracted with DCM (3×10 mL). The combined organic layerswere washed with brine (20 mL), dried over Na₂SO₄, filtered, and thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by MPLC (ISCO®; 4 g SepaFlash® Silica Flash Column, eluentof 0˜5% petroleum ether/EtOAc) to give the title compound. ¹H NMR (500MHz, CDCl3) δ 8.18-8.23 (m, 1H), 8.03-8.05 (m, 1H), 4.19-4.47 (m, 1H),2.96-3.10 (m, 1H), 2.51-2.60 (m, 4H).

Step 3:(R,E)-N-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)(3-(trifluoromethyl)cyclobutyl)methylene)-2-methylpropane-2-sulfinamide To a solution of(5-chloro-6-(trifluoromethyl)-pyridin-2-yl)(3-(trifluoromethyl)cyclobutyl)methanone (400 mg, 0.808 mmol) in toluene (6 ml) were addedtetraethoxytitanium (369 mg, 1.616 mmol) and(R)-2-methylpropane-2-sulfinamide (196 mg, 1.616 mmol). The mixture wasstirred at 105° C. for 1 hour in a microwave and then cooled to RT. Thereaction mixture was used as is in the next step without furtherpurification.

LRMS m/z (M+H): calculated 434.1, observed 435.1.

Step 4:(R)—N-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)(3-(trifluoromethyl)cyclobutyl)methyl)-2-methylpropane-2-sulfinamide(R,E)-N-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)(3-(trifluoromethyl)cyclobutyl)methylene)-2-methylpropane-2-sulfinamide(300 mg, crude) in toluene (6 ml) was diluted in THF (6 mL) and water(0.05 mL). Then NaBH₄ (131 mg, 3.45 mmol) was added and the mixture wasstirred at −70° C. for 1 hour. The reaction mixture was slowly warmed to27° C., and stirred for 15 hours. Then the mixture was diluted withwater (10 mL), filtered, and extracted with EtOAc (3×10 mL). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered and the filtrate was concentrated in vacuo. Theresulting residue was purified by Preparative TLC (SiO₂, petroleumether: EtOAc=2:1) to give the title compound. LRMS m/z (M+H): calculated436.1, observed 437.1.

Step 5:(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(3-(trifluoromethyl)cyclobutyl)methanaminehydrochloride To a solution of(R)—N-((5-chloro-6-(trifluoromethyl)pyridin-2-yl)(3-(trifluoro-methyl)cyclobutyl)methyl)-2-methylpropane-2-sulfinamide (300 mg, 0.549 mmol) in MeOH (3mL) was added HCl/MeOH (4 N, 3 mL). The mixture was stirred at 27° C.for 1 hour, then concentrated under reduced pressure to give the titlecompound. LRMS m/z (M+H): calculated 332.1, observed 333.1.

Step 6: Examples 47A, 47B, 47C and 47D To a solution of(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(3-(trifluoromethyl)cyclobutyl)methanamine hydrochloride (180 mg, 0.433 mmol) in DMF (3.5 mL) was addeddi(1H-imidazol-1-yl)methanone (140 mg, 0.866 mmol). The reaction mixturewas stirred at 27° C. for 1 hour, then (R)-3-methylpiperazin-2-one (51.9mg, 0.455 mmol) was added. The resulting mixture was stirred at 27° C.for 2 hours, then diluted with MeCN (1 mL) and purified by preparativeHPLC (62:38 to 32:68; water (0.1% TFA):MeCN (0.1% TFA)) to give amixture of isomers, which was separated by SFC (OJ-H column, 30%(EtOH+0.1% NH₃H₂O) co-solvent) to give first eluted isomer, Examples 47C(second eluted fraction) and 47D (third eluted fraction). The firsteluted isomer was further separated by second SFC (OJ-H column, 10-30%(EtOH+0.1% NH₃H₂O) co-solvent)) to give Examples 47A (first elutedfraction) and 47B (second eluted fraction).

Example 47A: LRMS m/z (M+H): calculated 472.1, observed 473.0. ¹H NMR δ(ppm) (400 MHz, Chloroform-d): 8.01 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.8Hz, 1H), 4.88 (d, J=10.4 Hz, 1H), 4.50-4.55 (m, 1H), 3.95-4.12 (m, 1H),3.34-3.41 (m, 1H), 3.19-3.29 (m, 2H), 2.75-2.99 (m, 2H), 2.28-2.37 (m,1H), 1.96-2.13 (m, 3H), 1.41 (d, J=7.2 Hz, 3H).

Example 47B: LRMS m/z (M+H): calculated 472.1, observed 473.1 ¹H NMR δ(ppm) (400 MHz, Chloroform-d): 8.02 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4Hz, 1H), 4.98 (d, J=11.2 Hz, 1H), 4.56-4.60 (m, 1H), 4.04-4.07 (m, 1H),3.31-3.34 (m, 1H), 3.26-3.30 (m, 2H), 2.96-3.26 (m, 2H), 2.30-2.35 (m,1H), 2.22-2.26 (m, 2H), 2.12-2.18 (m, 1H), 1.40 (d, J=7.2 Hz, 3H).

Example 47C: LRMS m/z (M+H): calculated 472.1, observed 473.0 ¹H NMR δ(ppm) (400 MHz, Chloroform-d): 8.01 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.4Hz, 1H), 4.88 (d, J=10.4 Hz, 1H), 4.50-4.55 (m, 1H), 3.95-4.12 (m, 1H),3.34-3.41 (m, 1H), 3.19-3.29 (m, 2H), 2.75-2.99 (m, 2H), 2.28-2.37 (m,1H), 1.96-2.13 (m, 3H), 1.43 (d, J=7.2 Hz, 3H).

Example 47D: LRMS m/z (M+H): calculated 472.1, observed 473.0 ¹H NMR δ(ppm) (400 MHz, Chloroform-d): 8.01 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.0Hz, 1H), 4.97 (d, J=10.4 Hz, 1H), 4.51-4.56 (m, 1H), 4.02-4.05 (m, 1H),3.32-3.40 (m, 1H), 3.19-3.28 (m, 2H), 2.87-3.08 (m, 2H), 2.30-2.39 (m,1H), 2.16-2.27 (m, 2H), 2.03-2.13 (m, 1H), 1.41 (d, J=7.2 Hz, 3H).

Examples 48A, 48B, 48C and 48D (2R)—N—((R orS)-1-(3-chloro-4-fluorophenyl)-1-(cis-3-(trifluoromethyl)cyclobutyl)ethyl)-2-methyl-3-oxopiperazine-1-carboxamide(48A), (2R)—N—((R orS)-1-(3-chloro-4-fluorophenyl)-1-(trans-3-(trifluoromethyl)cyclobutyl)ethyl)-2-methyl-3-oxopiperazine-1-carboxamide(48B), (2R)—N—((S orR)-1-(3-chloro-4-fluorophenyl)-1-(cis-3-(trifluoromethyl)cyclobutyl)ethyl)-2-methyl-3-oxopiperazine-1-carboxamide(48C) and (2R)—N—((S orR)-1-(3-chloro-4-fluorophenyl)-1-(trans-3-(trifluoromethyl)cyclobutyl)ethyl)-2-methyl-3-oxopiperazine-1-carboxamide(48D)

Step 1:1-(3-chloro-4-fluorophenyl)-1-(3-(trifluoromethyl)cyclobutyl)ethan-1-olMeMgBr (68.0 mg, 0.570 mmol) was added to a solution of(3-chloro-4-fluorophenyl)(3-(trifluoromethyl) cyclobutyl)methanone (20mg, 0.071 mmol) in THF (2.0 mL) at −78° C. The resulting mixture waswarmed to 25° C. slowly and stirred at 25° C. for 16 hours. Then thereaction was quenched with saturated aqueous NH₄Cl (5 mL) and extractedwith EtOAc (4×8 mL). The combined EtOAc layers were dried over Na₂SO₄,filtered and the filtrate was concentrated. The resulting residue waspurified by prep-TLC (SiO2, Pet.ether: EtOAc=5: 1) to give the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 7.62 (dd, J=2.0, 7.5 Hz, 1H),7.37-7.48 (m, 1H), 7.26-7.36 (m, 1H), 2.85-2.87 (m, 1H), 2.71-2.81 (m,1H), 2.41-2.43 (m, 1H), 1.95-2.12 (m, 2H), 1.64-1.66 (m, 1H), 1.38-1.28(m, 3H).

Step 2:2-chloro-N-(1-(3-chloro-4-fluorophenyl)-1-(3-(trifluoromethyl)cyclobutyl)ethyl)acetamide 2-chloroacetonitrile (153 mg, 2.022 mmol) was added to asolution of1-(3-chloro-4-fluorophenyl)-1-(3-(trifluoromethyl)cyclobutyl)ethan-1-ol(60 mg, 0.202 mmol) in TFA (1.5 mL) at 25° C. The resulting mixture wasstirred at 25° C. for 16 h, and then concentrated. The resulting residuewas purified by prep-HPLC (TFA) to give the title compound. ¹H NMR (400MHz, CDCl₃) δ 8.15-8.39 (m, 1H), 7.37 (t, J=2.4, 6.4 Hz, 1H), 7.20-7.28(m, 1H), 7.11-7.19 (m, 1H), 3.92-4.08 (m, 2H), 2.65-3.08 (m, 2H),1.93-2.31 (m, 4H), 1.62-1.68 (m, 3H).

Step 3:1-(3-chloro-4-fluorophenyl)-1-(3-(trifluoromethyl)cyclobutyl)ethan-1-amineA mixture of2-chloro-N-(1-(3-chloro-4-fluorophenyl)-1-(3-(trifluoromethyl)cyclobutyl)ethyl)acetamide (55 mg, 0.148 mmol) and thiourea (13.50 mg, 0.177 mmol)in EtOH (2 mL) and AcOH (0.400 mL) was stirred at 110° C. for 16 hours.Then the mixture was concentrated, and the resulting residue waspurified by prep-HPLC (50:50 to 20:80; water (0.1% TFA):MeCN (0.1% TFA))to give the title compound. LRMS m/z (M+H): calculated 295.1, observed296.1.

Step 4:(2R)—N-(1-(3-chloro-4-fluorophenyl)-1-(3-(trifluoromethyl)cyclobutyl)ethyl)-2-methyl-3-oxopiperazine-1-carboxamideTo a solution of triphosgene (25.07 mg, 0.095 mmol) in CH₂Cl₂ (5 mL) wasadded DIEA (0.124 mL, 0.710 mmol) at 0° C. Then a solution of1-(3-chloro-4-fluorophenyl)-1-(3-(trifluoromethyl)cyclobutyl)ethan-1-amine (70 mg, 0.237 mmol) in CH₂Cl₂ (1 mL) was added.The reaction mixture was stirred at 0° C. for 0.5 hour, then a solutionof (R)-3-methylpiperazin-2-one (32.4 mg, 0.284 mmol) in CH₂Cl₂ (1 mL)was added. The reaction mixture was stirred at 0° C. for 30 minutes, andthen concentrated. The resulting residue was purified by prep-HPLC(80:20 to 50:50; water (0.1% TFA):MeCN (0.1% TFA)) to give the titlecompound. LRMS m/z (M+H): calculated 435.1, observed 436.1.

Step 5: Examples 48A, 48B, 48C and 48D(2R)—N-(1-(3-chloro-4-fluorophenyl)-1-(3-(trifluoromethyl)cyclobutyl)ethyl)-2-methyl-3-oxopiperazine-1-carboxamide(75 mg, 0.172 mmol) was separated by Chiral SFC (Column: (S,S)-Whelk-O;5% to 40% of IPA with 0.05% DEA cosolvent) to give Examples 48A (firsteluted fraction) and 48B (second eluted fraction). The third elutedfraction which was further separated by second SFC (Column: OD-3, 5-40%EtOH with 0.05% DEA co-solvent) to give Examples 48C (first elutedfraction) and 48D (second eluted fraction).

Example 48A: LRMS m/z (M+H): calculated 435.1, observed 436.1. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.38 (dd, J=2.5, 7.0 Hz, 1H), 7.26-7.28(m, 1H), 7.12-7.21 (m, 1H), 4.53-4.65 (m, 1H), 3.95 (d, J=13.0 Hz, 1H),3.32-3.40 (m, 1H), 3.17-3.28 (m, 2H), 3.13-3.15 (m, 1H), 2.62-2.76 (m,1H), 2.12-2.34 (m, 3H), 2.06-2.08 (m, 1H), 1.76 (s, 3H), 1.40 (d, J=7.0Hz, 3H).

Example 48B: LRMS m/z (M+H): calculated 435.1, observed 436.1. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.37 (dd, J=2.5, 7.0 Hz, 1H), 7.24-7.26(m, 1H), 7.10-7.20 (m, 1H), 4.55-4.58 (m, 1H), 3.96-3.98 (m, 1H),3.34-3.45 (m, 1H), 3.20-3.29 (m, 2H), 2.94-3.05 (m, 1H), 2.75-2.89 (m,1H), 1.98-2.14 (m, 4H), 1.62 (s, 3H), 1.41 (d, J=7.0 Hz, 3H).

Example 48C: LRMS m/z (M+H): calculated 435.1, observed 436.1. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.37 (dd, J=2.5, 7.0 Hz, 1H), 7.25-7.28(m, 1H), 7.13-7.19 (m, 1H), 4.53-4.55 (m, 1H), 3.93-4.01 (m, 1H),3.32-3.41 (m, 1H), 3.15-3.28 (m, 3H), 2.67-2.69 (m, 1H), 2.14-2.32 (m,3H), 2.04-2.13 (m, 1H), 1.69 (s, 3H), 1.41 (d, J=7.0 Hz, 3H).

Example 48D: LRMS m/z (M+H): calculated 435.1, observed 436.1. ¹H NMR δ(ppm) (500 MHz, Chloroform-d): 7.36 (dd, J=2.5, 7.0 Hz, 1H), 7.23-7.25(m, 1H), 7.12-7.18 (m, 1H), 4.54-4.56 (m, 1H), 3.93-4.01 (m, 1H),3.32-3.41 (m, 1H), 3.19-3.29 (m, 2H), 3.05-3.08 (m, 1H), 2.84-2.86 (m,1H), 1.93-2.05 (m, 4H), 1.60 (s, 3H), 1.42 (d, J=7.0 Hz, 3H).

Examples 49A and 49B(2R)—N—((R)-(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamideand(2R)—N—((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide

Step 1:(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanoneTo a mixture ofN-methoxy-N-methyl-3-(trifluoromethyl)cyclobutane-1-carboxamide (50 mg,0.237 mmol) in THF (2 mL) was added(3-fluoro-4-(trifluoromethoxy)phenyl)magnesium bromide (134 mg, 0.474mmol) at 0° C. The mixture was stirred at 0° C. for 2 hours under N₂.Then the reaction was quenched with saturated aqueous NH₄Cl (10 mL) andextracted with EtOAc (3×10 mL). The combined organic layers were washedwith brine (20 mL), dried over anhydrous Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The resulting residuewas purified by prep-TLC (SiO₂, PE: EtOAc=20: 1) to give the titlecompound. ¹H NMR (500 MHz, CD₃CN) δ 7.73-7.77 (m, 1H), 7.67-7.73 (m,1H), 7.51-7.42 (m, 1H), 4.05-3.96 (m, 1H), 3.04-2.79 (m, 1H), 2.54-2.47(m, 2H), 2.46-2.40 (m, 2H).

Step 2:(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanolTEA (0.147 mL, 1.053 mmol) in DMF (1 mL) was added to a solution ofHCOOH (27.0 mg, 0.587 mmol) in DMF (2 mL) at 20° C. The resultingmixture was stirred at 20° C. for 10 min., then(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanone(60 mg, 0.173 mmol) in DMF (2 mL) was added, followed by the addition of(S,S)-Noyori's catalyst (1.098 mg, 1.726 μmol). The reaction was stirredat 20° C. for 16 hours, then quenched with water (10 mL) and extractedwith EtOAc (2×5 mL). The combined EtOAc layers were washed with brine(2×5 mL), dried over Na₂SO₄, and filtered. The filtrate wasconcentrated, and the resulting residue was purified by prep-TLC (PE:EtOAc=5:1) to give the title compound. ¹H NMR (400 MHz, CDCl3) δ7.27-7.23 (m, 1H), 7.18 (td, J=1.6, 10.8 Hz, 1H), 7.06-7.10 (m, 1H),4.66-4.55 (m, 1H), 2.67 (qd, J=7.6, 15.2 Hz, 1H), 2.36-2.22 (m, 2H),2.19-2.11 (m, 3H).

Step 3:(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methylmethanesulfonate Ms-Cl (0.279 mL, 3.58 mmol) was added to a solution of(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanol (55 mg, 0.157 mmol) andTEA (0.044 mL, 0.315 mmol) in THF (5 mL) cooled in an ice bath. Thereaction was stirred at 20° C. for 2.5 hours, then quenched with brine(10 mL) and extracted with EtOAc (2×5 mL). The combined EtOAc layerswere dried over Na₂SO₄, and filtered. The filtrate was concentrated togive the title compound.

Step 4:4-(azido(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-fluoro-1-(trifluoromethoxy)benzene NaN₃ (130 mg, 2.000 mmol) was added to a solution of(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl methanesulfonate (60mg, crude) in DMF (2.5 mL). The reaction was stirred at 80° C. for 16hours, then quenched with water (5 mL) and extracted with EtOAc (4×5mL). The combined EtOAc layers were washed with brine (2×10 mL), driedover Na₂SO₄, and filtered. The filtrate was concentrated to give thetitle compound.

Step 5:N-((3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-1,1,1-triphenyl-15-phosphaniminePPh₃ (62.4 mg, 0.238 mmol) was added to a solution of4-(azido(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-fluoro-1-(trifluoromethoxy) benzene (50 mg, crude)in THF (5 mL) and H₂O (1 mL). The reaction mixture was stirred at 65° C.for 16 hours, then concentrated to give the title compound. LRMS m/z(M+H): calculated 591.2, observed 592.1.

Step 6:(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanamineNaOH (47.7 mg, 1.192 mmol) was added to a mixture ofN-((3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-1,1,1-triphenyl-15-phosphanimine(70.5 mg crude) in MeOH (3 mL). The reaction mixture was stirred at 40°C. for 3 hours, then concentrated under reduced pressure. To theresulting residue was added water (10 mL), and the mixture was extractedwith DCM/MeOH (3×5 mL, 10:1). The combined organic layers were driedover Na₂SO₄, and filtered. The filtrate was concentrated, and theresulting residue was purified by prep-HPLC (70:30 to 40:60; water (0.1%TFA):MeCN (0.1% TFA)) to give the title compound. LRMS m/z (M+H-17):calculated 331.1, observed 315.0.

Step 7: Examples 49A and 49B A mixture of CDI (34.3 mg, 0.211 mmol) and(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanamine(35 mg, 0.106 mmol) in DMF (0.5 mL) was stirred at 20° C. for 1 hour.Then (R)-3-methylpiperazin-2-one (14.47 mg, 0.127 mmol) was added. Thereaction mixture was stirred at 20° C. for 1 hour, then filtered. Thefiltrate was purified by Prep-HPLC (51:49 to 31:69; water (0.1%TFA):MeCN (0.1% TFA)) to give a mixture of isomers, which was furtherseparated by SFC (AD-H column, 10% EtOH with 0.1% NH₃H₂O co-solvent) togive examples 49A (first eluted fraction) and 49B (second elutedfraction).

Example 49A: LRMS m/z (M+H): calculated 471.1, observed 472.2. ¹H NMR δ(ppm) (500 MHz, CD3CN): 7.36 (t, J=8.0 Hz, 1H), 7.25-7.29 (m, 1H), 7.20(d, J=8.5 Hz, 1H), 6.35 (br s, 1H), 5.53-5.61 (m, 1H), 4.75-4.79 (m,1H), 4.32 (q, J=7.0 Hz, 1H), 3.87-3.95 (m, 1H), 3.23-3.30 (m, 1H),3.08-3.19 (m, 2H), 2.96-3.05 (m, 1H), 2.72-2.81 (m, 1H), 2.27-2.36 (m,1H), 2.12 (br s, 1H), 1.96-2.02 (m, 2H), 1.31 (d, J=7.0 Hz, 3H).

Example 49B: LRMS m/z (M+H): calculated 471.1, observed 472.1. ¹H NMR δ(ppm) (500 MHz, CD3CN): 7.36 (t, J=8.0 Hz, 1H), 7.26-7.30 (m, 1H),7.17-7.25 (m, 1H), 6.35 (br s, 1H), 5.53-5.61 (m, 1H), 4.76-4.80 (m,1H), 4.37 (q, J=7.0 Hz, 1H), 3.90-3.98 (m, 1H), 3.19-3.27 (m, 1H),3.08-3.19 (m, 2H), 2.95-3.06 (m, 1H), 2.71-2.83 (m, 1H), 2.27-2.37 (m,1H), 2.12-2.16 (m, 1H), 1.98-2.04 (m, 2H), 1.31 (d, J=7.0 Hz, 3H).

TABLE 7 The following examples were prepared according to the syntheticprocedure for Examples 49A and 49B, using the appropriate startingmaterials and reagents Calc'd Observed Example Compound Name [M + H]⁺[M + H]⁺ Conditions 50A

((2R)-N-((R or S)-(2- fluoro-4-(trifluoro- methoxy)phenyl)(trans-3-(trifluoromethyl)- cyclobutyl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 471.1 472.1 SFC: AD-H Co-solvent: 15-40% EtOH peak 1 50B

(2R)-N-((S or R)-(2- fluoro-4-(trifluoro- methoxy)phenyl)(trans-3-(trifluoro-methyl)- cyclobutyl)-methyl)-2- methyl-3-oxopiperazine-1-carboxamide 471.1 472.1 SFC: AD-H Co-solvent: 15-40% EtOH peak 2 51A

(2R)-N-((R or S)-(4- fluoro-3-(trifluoro- methyl)phenyl)(trans-3-(trifluoro-methyl)-cyclo- butyl)methyl)-2-methyl- 3-oxo-piperazine-1-carboxamide 455.1 456.0 SFC: OJ-H Co-solvent: 15% EtOH peak 1 51B

(2R)-N-((S or R)-(4- fluoro-3-(trifluoro- methyl)phenyl)(trans-3-(trifluoro-methyl)- cyclobutyl)methyl)-2- methyl-3-oxopiperazine-1-carboxamide 455.1 456.0 SFC: OJ-H Co-solvent: 15% EtOH peak 2 52A

N-((R or S)-(4-fluoro-3- (trifluoromethyl)phenyl) (trans-3-(trifluoro-methyl)cyclobutyl)- methyl)-3-oxo- piperazine-1- carboxamide 441.1 442.1SFC: OJ-H Co-solvent: 20-40% EtOH peak 1 52B

N-((S or R)-(4-fluoro-3- (trifluoromethyl)phenyl) (trans-3-(trifluoro-methyl)cyclobutyl)- methyl)-3-oxo- piperazine-1- carboxamide 441.1 442.1SFC: OJ-H Co-solvent; 20-40% EtOH peak 2 53A

(2R)-N-((R or S)-(3- chloro-2-fluorophenyl)- (trans-3-(trifluoro-methyl)cyclobutyl)meth- yl)-2-methyl-3-oxo- piperazine-1- carboxamide421.1 422.0 SFC: (S,S)- Whelk-O1 Co-solvent: 5-40% EtOH with 0.05% DEApeak 1 53B

(2R)-N-((S or R)-(3- chloro-2-fluorophenyl)- (trans-3-(trifluoro-methyl)cyclobutyl)meth- yl)-2-methyl-3-oxo- piperazine-1- carboxamide421.1 422.0 SFC: (S,S)- Whelk-O1 Co-solvent: 5-40% EtOH with 0.05% DEApeak 2 54A

(2R)-N-((R or S)-(3- chloro-4-(trifluoro- methoxy)phenyl)(3-(trifluoromethyl)cyclo- butyl)methyl)-2-methyl- 3-oxopiperazine-1-carboxamide 487.8 488.5 SFC: AS-H Co-solvent: 10% EtOH Peak 1 54B

(2R)-N-((S or R)-(3- chloro-4-(trifluoro- methoxy)phenyl)(3-(trifluoromethyl)cyclo- butyl)methyl)-2-methyl- 3-oxopiperazine-1-carboxamide 487.8 488.5 SFC: AS-H Co-solvent: 10% EtOH peak 2

Examples 55A and 55B(2R)-2-methyl-3-oxo-N-((trans-4-(trifluoromethyl)cyclohexyl)((R)-2-(trifluoromethyl)thiazol-4-yl)methyl)piperazine-1-carboxamideand (2R)-2-methyl-3-oxo-N-((trans-4-(trifluoromethyl)cyclohexyl)((S)-2-(trifluoromethyl)thiazol-4-yl)methyl)piperazine-1-carboxamide

Step 1: 2-bromothiazole-4-carbaldehyde To a solution of ethyl2-bromothiazole-4-carboxylate (3.4 g, 14.40 mmol) in THF/CH₂Cl₂ (1:1, 30mL) was added DIBAL-H in toluene (1 M, 43.2 mL, 43.2 mmol) dropwise tomaintain the temperature −78° C. After 5 hours at −78° C., the reactionwas quenched with MeOH (5 mL), and the resulting mixture was poured intocold HCl (1 N, 20 mL). The aqueous phase was extracted with EtOAc (3×20mL), and the combined organic layers were dried with Na₂SO₄, filteredand concentrated under reduced pressure to give the title compound.

Step 2:(2-bromothiazol-4-yl)(trans-4-(trifluoromethyl)cyclohexyl)methanone To asolution of 2-bromothiazole-4-carbaldehyde (0.689 g, 3.59 mmol) in1,4-dioxane (20 mL) was added Cs₂CO₃ (1.462 g, 4.49 mmol) and4-methyl-N′-(4-(trifluoromethyl)cyclohexylidene)benzene-sulfonohydrazide(1 g, 2.99 mmol). The reaction mixture was stirred at 110° C. for 2hours, then diluted with water (20 mL) and extracted with EtOAc (3×20mL). The combined organic layers were washed with brine (20 mL), driedover anhydrous Na₂SO₄, filtered and concentrated. The resulting crudeproduct was purified by Preparative TLC (SiO₂, petroleum ether/ethylacetate=10/1) to give the title compound (first eluted isomer). ¹H NMR(500 MHz, CD30D) δ 8.24 (s, 1H), 3.52-3.59 (m, 1H), 2.08-2.16 (m, 1H),2.01-2.04 (m, 2H), 1.59-1.72 (m, 6H).

Step 3:(trans-4-(trifluoromethyl)cyclohexyl)(2-(trifluoromethyl)thiazol-4-yl)methanoneA mixture of(2-bromothiazol-4-yl)(trans-4-(trifluoromethyl)cyclohexyl)methanone (50mg, 0.146 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (33.7 mg,0.175 mmol) and CuI (2.78 mg, 0.015 mmol) in DMF (1 mL) was heated for10 hours at 100° C. and then concentrated under reduced pressure. Theresulting residue was purified by Preparative TLC (pet. ether/ethylacetate=10/1) to give the title compound. ¹H NMR (400 MHz, CDCl3) δ 8.38(s, 1H), 3.54 (s, 1H), 2.07-2.18 (m, 3H), 1.47-1.57 (m, 6H).

Step 4:(R)-2-methyl-N-((E)-(trans-4-(trifluoromethyl)cyclohexyl)(2-(trifluoromethyl)thiazol-4-yl)methylene)propane-2-sulfinamideTo a microwave tube was charged with(trans-4-(trifluoro-methyl)cyclohexyl)(2-(trifluoromethyl)thiazol-4-yl)methanone (200 mg, 0.604 mmol),(R)-2-methylpropane-2-sulfinamide (110 mg, 0.906 mmol), Ti(OEt)₄ (275mg, 1.207 mmol) and toluene (3 ml). The reaction mixture was microwavedat 110° C. for 60 minutes, and then cooled to RT, followed by theaddition of water (5 mL) and EtOAc (10 mL). The mixture was stirred for10 minutes, and then filtered through a Celite® pad. The separatedorganic layer was dried over Na₂SO₄, filtered and concentrated underreduced pressure to give the title compound.

LRMS m/z (M+H-17): calculated 434.1, observed 435.0.

Step 5:(R)-2-methyl-N-((trans-4-(trifluoromethyl)cyclohexyl)(2-(trifluoromethyl)thiazol-4-yl)methyl)propane-2-sulfinamideA solution of(R)-2-methyl-N-((E)-(trans-4-(trifluoromethyl)-cyclohexyl)(2-(trifluoromethyl)thiazol-4-yl)methylene)propane-2-sulfinamide (190 mg crude) in THF (2.5ml) and water (0.01 mL) was cooled to −78° C., followed by the additionof NaBH₄ (8.27 mg, 0.219 mmol). The reaction was stirred at −78° C. for5 minutes, then quenched with saturated aqueous NaHCO₃(6 mL) andextracted with EtOAc (3×10 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure to givethe title compound. LRMS m/z (M+H−17): calculated 436.1, observed 437.0.

Step 6:(trans-4-(trifluoromethyl)cyclohexyl)(2-(trifluoromethyl)thiazol-4-yl)methanaminehydrochloride A solution of(R)-2-methyl-N-((trans-4-(trifluoromethyl)cyclohexyl)(2-(trifluoromethyl)thiazol-4-yl)methyl)propane-2-sulfinamide(110 mg crude) in HCl-MeOH (3 mL) was stirred at 20° C. for 2 hours.Then the solvent was evaporated under reduced pressure to give the titlecompound. LRMS m/z (M+H−17): calculated 332.1, observed 333.0

Step 7: Examples 55A and 55B A mixture of CDI (29.3 mg, 0.181 mmol) and(trans-4-(trifluoromethyl)cyclohexyl)(2-(trifluoromethyl)thiazol-4-yl)methanaminehydrochloride (50 mg, 0.090 mmol) in DMF (1 mL) was stirred at 20° C.for 1 hour. Then (R)-3-methylpiperazin-2-one (11.34 mg, 0.099 mmol) wasadded. The resulting mixture was stirred at 20° C. for 1 hour and thenpurified by Prep-HPLC (50:50 to 30:70; water (0.1% TFA):MeCN (0.1% TFA))to give a mixture of isomers which was further separated by SFC ((s,s)WHELK-01, 30% EtOH with 0.1% NH₃H₂O co-solvent) to give examples 55A(first eluted fraction) and 55B (second eluted fraction).

Example 55A: LRMS m/z (M+H): calculated 472.1, observed 473.1. ¹H NMR δ(ppm) (500 MHz, CD30D): 7.71 (s, 1H), 4.81 (d, J=9.0 Hz, 1H), 4.55-4.60(m, 1H), 4.05 (d, J=14.5 Hz, 1H), 3.32-3.33 (m, 1H), 3.20-3.27 (m, 2H),2.05-2.15 (m, 2H), 1.95-2.04 (m, 2H), 1.91 (d, J=13.0 Hz, 1H), 1.39-1.41(m, 4H), 1.18-1.30 (m, 2H), 1.11-1.18 (m, 1H), 1.01-1.10 (m, 1H).

Example 55B: LRMS m/z (M+H): calculated 472.1, observed 473.1. ¹H NMR δ(ppm) (500 MHz, CD3OD): 7.70 (s, 1H), 4.78 (d, J=9.0 Hz, 1H), 4.51-4.59(m, 1H), 4.04 (d, J=13.5 Hz, 1H), 3.32-3.33 (m, 1H), 3.18-3.27 (m, 2H),2.04-2.16 (m, 2H), 1.94-2.03 (m, 2H), 1.87-1.93 (m, 1H), 1.42 (d, J=14.0Hz, 1H), 1.34-1.39 (m, 3H), 1.28-1.34 (m, 1H), 1.20-1.28 (m, 1H),1.10-1.18 (m, 1H), 1.01-1.10 (m, 1H).

Examples 56A, 56B, 56C and 56D(2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((3R,6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide,(2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((3S,6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide,(2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((3R,6R)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamideand (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((3S,6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide

Step 1:N-methoxy-N-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamideTo a stirred solution of6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxylic acid (300 mg, 1.514mmol), N,O-dimethyl hydroxylamine hydrochloride (148 mg, 1.514 mmol) andDIPEA (0.80 mL, 4.58 mmol) in DMF (5 mL) was added HATU (864 mg, 2.271mmol). Then reaction was stirred at 20° C. for 12 hours. Then thereaction mixture was diluted with EtOAc (30 mL), washed with water (2×20mL), and brine (10 mL). The separated organic layer was dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. The resulting residue was purified by pre-TLC(Pet.ether/EtOAc=3:1) to give the title compound. ¹H NMR (400 MHz,CDCl₃) δ 3.95-4.27 (m, 2H), 3.57-3.78 (m, 4H), 3.07-3.29 (m, 3H),2.74-2.86 (m, 0.4H), 2.42-2.55 (m, 0.6H), 2.09-2.23 (m, 1H), 1.54-1.89(m, 3H).

Step 2: 6-(trifluoromethyl)tetrahydro-2H-pyran-3-carbaldehyde To astirred solution ofN-methoxy-N-methyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-carboxamide(300 mg, 1.244 mmol) in CH₂Cl₂ (8 mL) was added DIBAL-H in toluene (1 M,2.487 mL, 2.487 mmol) at 0° C. The reaction was stirred at 0° C. for 3hours, then quenched with saturated aqueous NH₄Cl solution (10 mL). Themixture was diluted with DCM (20 mL), and washed with brine (10 mL). Theseparated organic layer was dried over anhydrous sodium sulfate,filtered and the filtrate was concentrated at 0° C. to give the titlecompound.

Step 3:(R)-2-methyl-N-((E)-(trans-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methylene)-propane-2-sulfinamideTo a stirred solution of6-(trifluoromethyl)tetrahydro-2H-pyran-3-carbaldehyde (140 mg) and(R)-2-methylpropane-2-sulfinamide (121 mg, 0.999 mmol) in THF (3 ml) wasadded tetraethoxytitanium (877 mg, 3.84 mmol) at 0° C. The reaction wasstirred at 20° C. for 12 hours, then poured into brine (10 mL) anddiluted with EtOAc (20 mL). The mixture was filtered through a Celite®pad, and the filtrate was washed with brine (5 mL). The organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure to give a residue, which was purified bypreparative-TLC (silica, Pet.ether/EtOAc=5:1) to give the titlecompound. LRMS m/z (M+H): calculated 285.1, observed 286.0.

Step 4:(R)—N-((3-chloro-2,4-difluorophenyl)(trans-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methylpropane-2-sulfinamideTo a stirred solution of(R)-2-methyl-N-((E)-(trans-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methylene)propane-2-sulfinamide(80 mg, 0.280 mmol) in THF (3.0 mL) was added(3-chloro-2,4-difluorophenyl)magnesium bromide (0.701 mL, 0.701 mmol) at0° C. The reaction was stirred at 0° C. for 3 hours, then quenched withsaturated aqueous NH₄Cl solution (5.0 mL) and extracted with EtOAc (2×10mL). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to give thetitle compound. LRMS m/z (M+H): calculated 433.1, observed 434.0.

Step 6:(3-chloro-2,4-difluorophenyl)(trans-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methanaminehydrochloride The mixture of(R)—N-((3-chloro-2,4-difluorophenyl)(trans-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methylpropane-2-sulfinamide(120 mg, crude) and HCl/MeOH (1 M, 3 mL) was stirred at 20° C. for 5hours. Then the solvent was removed under reduced pressure to give thetitle compound. LRMS m/z (M+H): calculated 329.1, observed 329.9.

Step 7: Examples 56A, 56B, 56C and 56D To a stirred solution of(3-chloro-2,4-difluoro-henyl)(trans-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methanaminehydrochloride (80 mg, 0.243 mmol) in DMF (2.0 ml) was added CDI (87 mg,0.534 mmol) at 20° C. After the addition was finished, the reactionmixture was stirred at 20° C. for 1 hour, followed by the addition of(R)-3-methylpiperazin-2-one (36.0 mg, 0.315 mmol). The reaction mixturewas stirred at 20° C. for 2 hours and then purified by preparative HPLC(62:38 to 42:58; water (0.1% TFA):MeCN (0.1% TFA)) to give isomer A(first eluted fraction) and isomer B (second eluted fraction). Isomer Awas further separated by SFC (OJ-H column, 25% EtOH with 0.1% NH₃H₂Oco-solvent) to give Examples 56A (first eluted fraction) and 56B (secondeluted fraction). Isomer B was further separated by SFC (OJ-H column,25% EtOH with 0.1% NH₃H₂O co-solvent) to give Examples 56C (first elutedfraction) and 56D (second eluted fraction).

Example 56A: LRMS m/z (M+H): calculated 469.1, observed 470.2. ¹H NMR δ(ppm) (400 MHz, CD30D): 7.36 (dd, J=8.0, 6.0 Hz, 1H), 7.11 (dd, J=8.0,1.6 Hz, 1H), 4.75-4.81 (m, 1H), 4.47-4.63 (m, 2H), 4.00 (d, J=13.2 Hz,1H), 3.76-3.84 (m, 1H), 3.47 (d, J=10.0 Hz, 1H), 3.33 (d, J=3.2 Hz, 1H),3.17-3.24 (m, 2H), 2.26 (d, J=13.2 Hz, 1H), 2.07-2.17 (m, 1H), 1.85-1.94(m, 1H), 1.51-1.62 (m, 1H), 1.34-1.48 (m, 4H).

Example 56B: LRMS m/z (M+H): calculated 469.1, observed 470.2. ¹H NMR δ(ppm) (400 MHz, CD3OD): 7.29-7.38 (m, 1H), 7.11 (t, J=8.8 Hz, 1H), 4.77(d, J=10.0 Hz, 1H), 4.59 (s, 1H), 4.48 (q, J=6.8 Hz, 1H), 3.99 (d,J=13.2 Hz, 1H), 3.76-3.86 (m, 1H), 3.47 (d, J=10.0 Hz, 1H), 3.34 (d,J=3.6 Hz, 1H), 3.16-3.27 (m, 2H), 2.28 (d, J=13.2 Hz, 1H), 2.07-2.17 (m,1H), 1.89 (d, J=13.2 Hz, 1H), 1.52-1.63 (m, 1H) 1.28-1.48 (m, 4H).

Example 56C: LRMS m/z (M+H): calculated 469.1, observed 470.2. ¹H NMR δ(ppm) (400 MHz, CD30D): 7.33-7.40 (m, 1H), 7.08-7.17 (m, 1H), 4.81 (d,J=10.8 Hz, 1H), 4.58 (s, 1H), 4.48-4.56 (m, 1H), 4.32 (d, J=10.8 Hz,1H), 4.00 (d, J=12.8 Hz, 1H), 3.77-3.86 (m, 1H), 3.34-3.43 (m, 1H),3.19-3.29 (m, 2H), 2.02-2.15 (m, 1H), 1.79 (d, J=13.6 Hz, 1H), 1.25-1.55(m, 6H).

Example 56D: LRMS m/z (M+H): calculated 469.1, observed 470.2. ¹H NMR δ(ppm) (400 MHz, CD30D): 7.29-7.38 (m, 1H), 7.11 (dd, J=8.8, 1.6 Hz, 1H),4.78 (d, J=11.2 Hz, 1H), 4.58 (s, 1H), 4.46 (q, J=6.8 Hz, 1H), 4.31 (d,J=11.2 Hz, 1H), 3.97 (d, J=13.6 Hz, 1H), 3.74-3.85 (m, 1H), 3.31-3.39(m, 1H), 3.16-3.26 (m, 2H), 2.09-2.20 (m, 1H), 1.77 (d, J=11.2 Hz, 1H),1.15-1.59 (m, 6H).

Examples 57A, 57B, 57C and 57D(2R)—N—(R)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide,(2R)—N—(R)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide,(2R)—N—(S)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamideand(2R)—N—(S)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide

Step 1: (E)-4,4,4-trifluoro-N-methoxy-N-methylbut-2-enamide To asolution of (E)-4,4,4-trifluorobut-2-enoic acid (5 g, 35.7 mmol) in DCM(80 ml) were added N-ethyl-N-isopropyl-propan-2-amine (18.70 ml, 107mmol), EDCI (10.27 g, 53.5 mmol) and N,O-dimethylhydroxyl-aminehydrochloride (5.22 g, 53.5 mmol). The reaction mixture was stirred at20° C. for 15 hours, then diluted with water (60 mL) and extracted withDCM (2×40 mL). The combined organic layers were washed with HCl (2 N, 20mL) and brine (50 mL). The separated organic layer was dried overNa₂SO₄, filtered and concentrated under reduced pressure to give thetitle compound. ¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J=12.4 Hz, 1H),6.78-6.86 (m, 1H), 3.77 (s, 3H), 3.30 (s, 3H).

Step 2:trans-N-methoxy-N-methyl-2-(trifluoromethyl)cyclopropane-1-carboxamideTo a solution of trimethylsulfoxonium iodide (10.09 g, 45.9 mmol) inDMSO (60 ml) was added sodium hydride (1.835 g, 45.9 mmol). Theresulting mixture was stirred at 20° C. for 1 hour, followed by theaddition of (E)-4,4,4-trifluoro-N-methoxy-N-methylbut-2-enamide (6 g,22.93 mmol) in DMSO (30 ml). The reaction mixture was stirred at 20° C.for 1 hour, then diluted with water (20 mL) and extracted with DCM (2×10mL). The combined organic layers were washed with brine (20 mL), driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by MPLC (ISCO®; 12 g SepaFlash® SilicaFlash Column, eluent of 0˜30% petroleum ether/EtOAc gradient) to givethe title compound. ¹H NMR (400 MHz, CDCl₃) δ 3.77 (s, 3H), 3.23 (s,3H), 2.51-2.59 (m, 1H), 2.10-2.16 (m, 1H), 1.34-1.38 (m, 1H), 0.84-0.88(m, 1H).

Step 3:((3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)methanoneTo a solution of isopropylmagnesium chloride (24.25 ml, 48.5 mmol) inTHF (24.25 ml) at 0° C. was added 1-bromo-3-chloro-2,4-difluorobenzene(13.24 g, 58.2 mmol). The mixture was stirred at 0° C. for 2.5 hours,thentrans-N-methoxy-N-methyl-2-(trifluoromethyl)cyclopropane-1-carboxamide(4.5 g, 19.40 mmol) in THF (30 mL) was added at 0° C. The reactionmixture was stirred at 20° C. for 12 hours, then saturated aqueous NH₄Clsolution (40 mL) was added, and the mixture was diluted with water (20mL), and extracted with EtOAc (3×40 mL). The combined organic layerswere washed with brine (40 mL), dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The resulting residuewas purified by MPLC (ISCO®; 12 g SepaFlash® Silica Flash Column, eluentof 0˜2% Pet. ether/EtOAc) to give the title compound. ¹H NMR (400 MHz,CDCl₃) δ 7.73-7.77 (m, 1H), 6.96-7.02 (m, 1H), 2.97-3.02 (m, 1H),2.39-2.43 (m, 1H), 1.56-1.59 (m, 1H), 1.47-1.51 (m, 1H).

Step 4:(R)—N—((Z)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)methylene)-2-methylpropane-2-sulfinamide To a solution of((3-chloro-2,4-difluorophenyl)-(trans-2-(trifluoromethyl)cyclopropyl)methanone(1 g, 3.51 mmol) in toluene (5 ml) were added(R)-2-methylpropane-2-sulfinamide (0.639 g, 5.27 mmol) andtetraethoxytitanium (1.202 g, 5.27 mmol). The reaction mixture wasstirred at 105° C. for 30 minutes in the microwave, then diluted withwater (10 mL) and EtOAc (10 mL), and filtered. The filtrate wasextracted with EtOAc (2×10 mL). The combined organic layers were washedwith brine (20 mL), dried over Na₂SO₄, and filtered. The filtrate wasconcentrated under reduced pressure to give the title compound. ¹H NMR(400 MHz, CDCl₃) δ 7.73-7.77 (m, 1H), 6.96-7.02 (m, 1H), 2.97-3.02 (m,1H), 2.39-2.43 (m, 1H), 1.56-1.59 (m, 1H), 1.47-1.51 (m, 1H). LRMS m/z(M+H): calculated 387.1, observed 388.0.

Step 5: (R)—N—((S orR)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)methyl)-2-methylpropane-2-sulfinamide (isomer A) and (R)—N—((R orS)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)methyl)-2-methylpropane-2-sulfinamide(isomer B) To a solution of(R)—N—((Z)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)-cyclopropyl)methylene)-2-methylpropane-2-sulfinamide (1 g, crude) in THF (15 mL) andwater (1 mL) was added NaBH₄ (0.293 g, 7.74 mmol) at −70° C. Thereaction mixture was stirred at −70° C. for 2 hours, then quenched withwater (10 ml) and extracted with EtOAc (2×10 mL). The combined organiclayers were washed with brine (20 mL), dried over Na₂SO₄, filtered andthe filtrate was concentrated under reduced pressure. The resultingresidue was purified by MPLC (ISCO®; 12 g SepaFlash® Silica FlashColumn, eluent of 0˜50% petroleum ether/EtOAc) to give isomer A (firsteluted fraction) and isomer B (second fraction). Isomer A: LRMS m/z(M+H): calculated 389.1, observed 390.0. Isomer B: LRMS m/z (M+H):calculated 389.1, observed 390.0.

Step 6: ((S orR)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)methanamine hydrochloride (isomer C) A solution ofR)—N—((S)-(3-chloro-2,4-difluorophenyl)-(trans-2-(trifluoromethyl)cyclopropyl)methyl)-2-methylpropane-2-sulfinamide (isomer A, 200 mg, 0.513 mmol) inHCl/MeOH (4 N, 3 mL) was stirred at 29° C. for 1 hour. Then the reactionmixture was concentrated under reduced pressure to give the titlecompound. LRMS m/z (M+H): calculated 285.0, observed 285.9.

Step 7: Examples 57A, 57B, 57C and 57D To a solution of((S)-(3-chloro-2,4-difluorophenyl)-(trans-2-(trifluoromethyl)cyclopropyl)methanamine hydrochloride (isomer C, 100 mg crude) in DMF (2 ml) wereadded triethylamine (70.9 mg, 0.700 mmol), anddi(1H-imidazol-1-yl)methanone (114 mg, 0.700 mmol). The reaction wasstirred at 29° C. for 1 hour, then (R)-3-methylpiperazin-2-one (40.0 mg,0.350 mmol) was added, and the mixture was stirred at 29° C. for 1 hour.The mixture was then diluted with MeCN (2 mL) and purified by Prep. HPLC(70:30 to 40:60; water (0.1% TFA):MeCN (0.1% TFA)) to give a mixture ofisomers, which was further separated by SFC (OJ_H column, 30% EtOH with0.1% NH₃H₂O co-solvent) to give Examples 57A (first eluted fraction) and57B (second eluted fraction).

Examples 57C and 57D were prepared according to the synthetic procedurefor Examples 57A and 57B using isomer B in step 6. Examples 57C (firsteluted fraction) and 57D (second eluted fraction) were separated by SFC(OJ-H column, 30% EtOH with 0.1% NH₃H₂O co-solvent).

Example 57A: LRMS m/z (M+H): calculated 425.1, observed 426.0. ¹H NMR δ(ppm) (400 MHz, CD30D): 7.45-7.49 (m, 1H), 7.11-7.16 (m, 1H), 4.60-4.63(m, 1H), 4.51-4.54 (m, 1H), 4.00-4.03 (m, 1H), 3.33-3.36 (m, 1H),3.25-3.29 (m, 2H), 1.80-1.89 (m, 2H), 1.40 (d, J=7.2 Hz, 3H), 1.01-1.04(m, 1H), 0.93-1.00 (m, 1H).

Example 57B: LRMS m/z (M+H): calculated 425.1, observed 426.0. ¹H NMR δ(ppm) (400 MHz, CD3OD): 77.48-7.52 (m, 1H), 7.11-7.16 (m, 1H), 4.55-4.62(m, 2H), 4.03-4.07 (m, 1H), 3.34-3.36 (m, 1H), 3.20-3.27 (m, 2H),1.77-1.87 (m, 2H), 1.43 (d, J=7.2 Hz, 3H), 1.03-1.06 (m, 1H), 0.96-1.02(m, 1H).

Example 57C: LRMS m/z (M+H): calculated 425.1, observed 426.0. ¹H NMR δ(ppm) (400 MHz, CD30D): 7.43-7.46 (m, 1H), 7.11-7.16 (m, 1H), 4.52-4.60(m, 2H), 4.00-4.03 (m, 1H), 3.33-3.36 (m, 1H), 3.24-3.27 (m, 2H),1.72-1.76 (m, 2H), 1.41 (d, J=7.2 Hz, 3H), 1.06-1.14 (m, 2H).

Example 57D: LRMS m/z (M+H): calculated 425.1, observed 426.0. ¹H NMR δ(ppm) (400 MHz, CD30D): 7.42-7.45 (m, 1H), 7.11-7.16 (m, 1H), 4.50-4.56(m, 2H), 4.02-4.05 (m, 1H), 3.33-3.36 (m, 1H), 3.24-3.28 (m, 2H),1.73-1.79 (m, 2H), 1.40 (d, J=6.8 Hz, 3H), 1.07-1.14 (m, 2H).

Examples 58A, 58B, 58C and 58D (2R)—N—((R orS)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(58A), (2R)—N—((R orS)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(58B), (2R)—N—((R orS)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(58C) and (2R)—N—((R orS)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(58D)

Step 1: N-methoxy-N-methyl-3-(trifluoromethyl)cyclopentane-1-carboxamideTo a solution of CDI (1602 mg, 9.88 mmol) in DCM (10 mL) was added3-(trifluoromethyl) cyclopentane-1-carboxylic acid (900 mg, 4.94 mmol)at 20° C. The mixture was stirred for 1 h. Then DIEA (2.59 mL, 14.82mmol) and N,O-dimethyl hydroxylamine hydrochloride (578 mg, 5.93 mmol)were added, and the resulting mixture was stirred at 20° C. for another2 h. Water (20 mL) was added, and the mixture was extracted with DCM(3×10 mL). The combined organic fractions were washed with brine (10mL), dried over Na₂SO₄, filtered and the filtrate was evaporated underreduced pressure. The resulting crude product was purified by flashsilica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column,eluent of 24% petroleum ether/ethyl acetate) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ 3.67 (s, 3H), 3.17 (s, 2H), 3.12-3.23 (m, 4H),2.51-2.69 (m, 1H), 1.89-2.16 (m, 4H).

Step 2:(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclopentyl)methanon Toa solution of 1-bromo-3-chloro-2,4-difluorobenzene (3.28 g, 14.43 mmol)in THF (10 mL) was added isopropyl magnesium chloride (6.35 mL, 12.70mmol) at 0° C. The reaction mixture was stirred for 2 h, thenN-methoxy-N-methyl-3-(trifluoromethyl)cyclopentane-1-carboxamide (1.3 g,5.77 mmol) in THF (6 mL) was added. The reaction was stirred at 0° C.for 12 hours, then quenched with saturated aqueous NH₄Cl (20 mL) andextracted with ethyl acetate (3×10 mL). The combined organic layers werewashed with brine (20 mL), dried over Na₂SO₄, and filtered. The filtratewas evaporated under reduced pressure, and the resulting crude productwas purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash®Silica Flash Column, Eluent of 1% petroleum ether/ethyl acetate) to givethe title compound. ¹H NMR (500 MHz, CDCl₃) δ 7.76-7.83 (m, 1H),7.06-7.12 (m, 1H), 3.61-3.70 (m, 1H), 2.68-2.80 (m, 1H), 2.20-2.29 (m,1H), 2.07-2.14 (m, 1H), 1.92-2.05 (m, 3H), 1.83-1.91 (m, 1H).

Step 3:(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclopentyl)methanolEt₃N (2.140 mL, 15.35 mmol) in DMF (5 mL) was added to a solution offormic acid (0.338 mL, 8.96 mmol) in DMF (5 mL) at 25° C. The resultingmixture was stirred at 25° C. for 10 minutes. Then(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclopentyl)methanone(1 g, 2.56 mmol) in DMF (5.00 mL) was added to the mixture, followed bythe addition of (s,s)-n-(p-toluenesulfonyl)-1,2-diphenylethanediamine(chloro) (p-cymene) ruthenium (ii) (0.016 g, 0.026 mmol). The reactionwas stirred at 25° C. for 16 hours, then quenched with water (6 mL) andextracted with EtOAc (4×6 mL). The combined EtOAc layers were dried overNa₂SO₄, and filtered. The filtrate was concentrated under reducedpressure, and the resulting crude product was purified by flash silicagel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, eluentof 34% petroleum ether/ethyl acetate) to give the title compound. ¹H NMR(400 MHz, CDCl₃) δ 7.42-7.54 (m, 1H), 7.30 (t, J=8.8 Hz, 1H), 5.54-5.68(m, 1H), 4.54-4.81 (m, 1H), 2.70-2.95 (m, 1H), 2.21-2.23 (m, 1H),1.27-1.94 (m, 6H).

Step 4:(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclopentyl)methylmethanesulfonate Ms-Cl (0.297 mL, 3.81 mmol) was added to a solution of(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclopentyl)methanol(800 mg, 2.54 mmol) and Et₃N (0.709 mL, 5.08 mmol) in THF (12 mL) cooledin an ice bath. The reaction was stirred at 15° C. for 2 hours, thenquenched with brine (50 mL) and extracted with EtOAc (4×10 mL). Thecombined EtOAc layers were dried over Na₂SO₄, filtered, and the filtratewas concentrated to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ7.30-7.40 (m, 1H), 7.01-7.13 (m, 1H), 5.58-5.67 (m, 1H), 3.68 (s, 1H),2.85-2.87 (m, 3H), 2.48-2.78 (m, 2H), 1.79-1.95 (m, 2H), 1.60-1.77 (m,2H), 1.31-1.49 (m, 1H).

Step 5:1-(azido(3-(trifluoromethyl)cyclopentyl)methyl)-3-chloro-2,4-difluorobenzenSodium azide (99 mg, 1.528 mmol) was added to a solution of(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclopentyl)methylmethanesulfonate (200 mg, 0.509 mmol) in DMF (2.5 mL). The reaction wasstirred at 50° C. for 16 hours, then quenched with water (15 mL) andextracted with EtOAc (4×10 mL). The combined EtOAc layers were washedwith brine (2×5 mL), dried over Na₂SO₄, filtered, and the filtrate wasconcentrated to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ7.23-7.32 (m, 1H), 7.00-7.08 (m, 1H), 4.59-4.70 (m, 1H), 2.54-2.76 (m,1H), 2.27-2.43 (m, 1H), 1.91-2.07 (m, 1H), 1.46-1.84 (m, 4H), 1.29-1.45(m, 1H).

Step 6:(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclopentyl)methanaminePPh₃ (174 mg, 0.662 mmol) was added to a solution of1-(azido(3-(trifluoromethyl)cyclopentyl)methyl)-3-chloro-2,4-difluorobenzene (150 mg, 0.442 mmol) in THF (2.5mL) and H₂O (0.5 mL). The reaction was stirred at 65° C. for 16 hours,then cooled to room temperature, followed by the addition of water (20mL). The mixture was extracted with ethyl acetate (3×10 mL). Thecombined organic layers were washed with brine (20 mL), dried overNa₂SO₄, filtered, and the solvent was evaporated under reduced pressure.The resulting residue was purified by reverse phase HPLC (75:25 to55:45; water (0.1% TFA):MeCN (0.1% TFA)), followed by lyophilization togive the title compound. LRMS m/z (M+H): calculated 313.1, observed314.1.

Step 7: Examples 58A, 58 B, 58C and 58D A mixture of(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclopentyl)methanamine(80 mg, 0.255 mmol), CDI (41.4 mg, 0.255 mmol) and DIEA (0.045 mL, 0.255mmol) in DMF (1 mL) was stirred at 20° C. for 1 hour, then(R)-3-methylpiperazin-2-one (29.1 mg, 0.255 mmol) in DMF (0.5 mL) wasadded. The resulting mixture was stirred at 20° C. for 1 hour, and thenpurified by reverse phase HPLC (50:50 to 20:80; water (0.1% TFA):MeCN(0.1% TFA)) followed by lyophilization to give four fractions: Firsteluted fraction gave example 58A; Second eluted fraction was furtherseparated by SFC (AS-H column, 15-35% (0.1% NH₃H₂O+EtOH) as cosolvent)to give example 58B; Third eluted fraction gave example 58C; Fourtheluted fraction was further separated by SFC (AS-H column, 15-35% (0.1%NH₃H₂O+EtOH) as cosolvent) to give Example 58D.

Example 58A: LRMS m/z (M+H): calculated 453.1, observed 454.1. ¹H NMR δ(ppm) (400 MHz, CD30D): 7.30-7.42 (m, 1H), 7.10 (t, J=8.8 Hz, 1H), 4.84(s, 1H), 4.40-4.55 (m, 1H), 3.99-4.01 (m, 1H), 3.31-3.37 (m, 1H),3.15-3.28 (m, 2H), 2.63-2.79 (m, 1H), 2.42-2.58 (m, 1H), 1.99-2.11 (m,1H), 1.80-1.97 (m, 2H), 1.50-1.64 (m, 2H), 1.37 (d, J=7.2 Hz, 3H),1.21-1.33 (m, 1H). Example 58B: LRMS m/z (M+H): calculated 453.1,observed 454.1. ¹H NMR δ (ppm) (400 MHz, CD30D): 7.29-7.43 (m, 1H),7.04-7.15 (m, 1H), 4.84-4.86 (m, 1H), 4.49 (q, J=7.2 Hz, 1H), 4.0-4.03(m, 1H), 3.31-3.38 (m, 1H), 3.15-3.28 (m, 2H), 2.69-2.86 (m, 1H),2.41-2.56 (m, 1H), 2.21-2.32 (m, 1H), 1.74-1.90 (m, 2H), 1.27-1.53 (m,6H). Example 58C: LRMS m/z (M+H): calculated 453.1, observed 454.1. ¹HNMR δ (ppm) (400 MHz, CD30D): 7.33-7.40 (m, 1H), 7.11 (t, J=8.4 Hz, 1H),4.83 (d, J=10.8 Hz, 1H), 4.49 (d, J=6.4 Hz, 1H), 3.99-4.02 (m, 1H),3.34-3.36 (m, 1H), 3.16-3.27 (m, 2H), 2.74-2.88 (m, 1H), 2.47-2.61 (m,1H), 2.00-2.16 (m, 2H), 1.66-1.78 (m, 1H), 1.44-1.57 (m, 3H), 1.37 (d,J=7.2 Hz, 3H). Example 58D: LRMS m/z (M+H): calculated 453.1, observed454.1. ¹H NMR δ (ppm) (400 MHz, CD30D): 7.29-7.42 (m, 1H), 7.10 (t,J=8.4 Hz, 1H), 4.82 (d, J=10.8 Hz, 1H), 4.49 (q, J=7.2 Hz, 1H),3.99-4.02 (m 1H), 3.32-3.38 (m, 1H), 3.17-3.28 (m, 2H), 2.86-2.90 (m,1H), 2.52-2.54 (m, 1H), 2.05-2.15 (m, 1H), 1.93-2.04 (m, 1H), 1.73-1.84(m, 1H), 1.57-1.70 (m, 1H), 1.45 (br s, 1H), 1.37 (d, J=7.2 Hz, 3H),1.28 (br s, 1H).

Intermediate 1(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanaminehydrochloride

Step 1:(R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methylpropane-2-sulfinamideTo a solution of(R,E)-N-((3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)cyclobutyl)methylene)-2-methylpropane-2-sulfinamide (8.0 g, 20 mmol, seepreparation in step 2 for Examples 20A-20D) in THF (80 mL) at −78° C.under an inert atmosphere of N₂ was added DIBAL-H (50 mL, 50 mmol, 1M)dropwise. The reaction mixture was stirred at −78° C. for 2 hours. Anaqueous solution of NH₄Cl (50 mL) was added at −78° C., then the mixturewas warmed to 40° C. After 20 minutes the mixture was filtered through apad of Celite™ and the filtrate was rinsed with ethyl acetate (5×50 mL).The resulting mixture was extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby silica gel chromatography (1-17% ethyl acetate/petroleum ether) togive the title compound.

Step 2:(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanaminehydrochloride To a solution of(R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)-cyclobutyl)-methyl)-2-methylpropane-2-sulfinamide (63 g, 0.16 mol) in CH₂Cl₂ (0.63 L) at 0° C. wasadded HCl in ethyl acetate (4 M, 0.26 L, 3.1 mol). The reaction mixturewas stirred at 0° C. for 2 hours and then concentrated under reducedpressure. The resulting residue was treated with methyl tert-butyl ether(100 mL), stirred 20 minutes at 25° C. and filtered to give the titlecompound.

Intermediate 2(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanamine

(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanamineThe free base(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)-cyclobutyl)-methanamineis formed by washing a solution of(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)-cyclobutyl)methanaminehydrochloride in an organic solvent such as ethyl acetate with a basicaqueous solution such as potassium carbonate, sodium bicarbonate orsodium hydroxide. The resulting organic layer is dried over Na₂SO₄,filtered and concentrated under reduced pressure to give(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)-cyclobutyl)methanamine.

Intermediate 3(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methanamineoxalate

To a solution of(S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methanamine(0.50 g, 1.7 mmol) in THF (1.5 mL) at 25° C. was added a solution ofoxalic acid (0.15 g, 1.7 mmol) in THF (1.5 mL). After 12 hours, theresulting mixture was filtered to give the title compound.

Example 59A and 59B (R orS)—N—((S)-(3-chloro-2,4-difluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-5,5,6,6-d4-1-carboxamide(59A) and (S orR)—N—((S)-(3-chloro-2,4-difluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-5,5,6,6-d4-1-carboxamide(59B)

Step 1: methyl (S)-2-bromopropanoate To a solution of(S)-2-bromopropanoic acid (4.0 g, 26 mmol) in MeOH (25 ml) and DCM (50ml) at 15° C. was added (diazomethyl)trimethylsilane (45 ml, 90 mmol, 2M in hexane). The resulting mixture was stirred at 15° C. for 1 hour andthen concentrated under reduced pressure to give the title compoundwhich was used in the next step without further purification. 1H NMR(500 MHz, CDCl₃) δ (ppm): 4.39 (q, J=7.0 Hz, 1H), 3.79 (s, 3H), 1.84 (d,J=7.0 Hz, 3H).

Step 2: 3-methylpiperazin-2-one-5,5,6,6-d4 To a solution ofethane-d4-1,2-diamine (0.30 g, 4.7 mmol) in dioxane (5.5 mL) at 15° C.were added sodium hydrogencarbonate (0.59 g, 7.0 mmol) and(S)-2-bromopropanoate (0.39 g, 2.3 mmol). The mixture was stirred at 15°C. for 1 hour, then at 50° C. for 24 hours. Then the mixture wasconcentrated under reduced pressure, and the resulting residue waspurified by silica gel chromatography, eluting with 10/1/0.1DCM/MeOH/NH₃.H₂O to give the title compound. 1H NMR (500 MHz, CD3OD) δ(ppm): 3.40-3.42 (m, 1H), 1.33-13.35 (m, 3H).

Step 3: Example 59 A mixture of CDI (0.38 g, 2.3 mmol) and(S)-(3-chloro-2,4-difluorophenyl)-((trans)-3-(trifluoromethyl)cyclobutyl)methanamineoxalate (Intermediate 3, 0.35 g, 1.2 mmol) in DMF (4 mL) was stirred at25° C. for 5 minutes, then 3-methylpiperazin-2-one-5,5,6,6-d4 (0.19 g,1.6 mmol) was added. The resulting mixture was stirred at 25° C. for 30minutes, and then filtered. The filtrate was purified by reverse phaseHPLC (Phenomenex Synergi C18 column, 65:35 to 35:65; water containing 10mM NH₄HCO₃: acetonitrile) to give a residue, that was further separatedby SFC (Daicel Chiralpak AD-H column, 20% IPA as cosolvent) to giveExamples 59A (first eluted peak) and 59B (second eluted peak).

Example 59A: LRMS m/z (M+H): calculated 444.1, observed 444.1. 1H NMR(400 MHz, CD3OD) δ (ppm): 7.29-7.35 (m, 1H), 7.08-7.12 (m, 1H), 5.08 (d,J=11.2 Hz, 1H), 4.46-4.52 (m, 1H), 3.01-3.05 (m, 1H), 2.90 (s, 1H),2.24-2.38 (m, 1H), 2.20-2.22 (m, 1H), 1.94-2.04 (m, 2H), 1.37 (d, J=8.8Hz, 3H).

Example 59B: LRMS m/z (M+H): calculated 444.1, observed 444.2. 1H NMR(400 MHz, CD3OD) δ (ppm): 7.31-7.35 (m, 1H), 7.08-7.12 (m, 1H), 5.10 (d,J=11.5 Hz, 1H), 4.52 (q, J=7.0 Hz, 1H), 3.00-3.08 (m, 1H), 2.81-2.95 (m,1H), 2.34-2.40 (m, 1H), 2.16-2.27 (m, 1H), 2.00-2.09 (m, 1H), 1.91-2.00(m, 1H), 1.38 (d, J=7.0 Hz, 3H).

Examples 60A and 60B (2R)—N-((1(R orS))-(4-fluoro-3-(trifluoromethyl)phenyl)-trans-(6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(60A) and (2R)—N-((1(R orS))-(4-fluoro-3-(trifluoromethyl)phenyl)-trans-(6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide(60B)

Step 1:(R)—N-((5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methylpropane-2-sulfinamideTo a solution of 6-bromo-3-fluoro-2-(trifluoromethyl)-pyridine (0.26 g,1.1 mmol) in dry THF (5 mL) at 0° C. was added dropwise iPrMgCl (0.50ml, 1.0 mmol). The mixture was stirred at 0° C. for 25 minutes and thentransferred dropwise to a 0° C. solution of(R)-2-methyl-N-((E)-(6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methylene)propane-2-sulfinamide(0.15 g, 0.53 mmol) in dry THF (8 ml). The resulting mixture wasgradually allowed to warm to rt and then stirred for 18 h. Then waterwas added and the resulting mixture was extracted with EtOAc (3×10 mL).The combined organic layers were dried over Na₂SO₄, filtered andevaporated under reduced pressure. The resulting crude residue waspurified by reverse phase HPLC (85:15 to 5:95; water containing 0.1%TFA: acetonitrile containing 0.1% TFA) to give the title compound. LRMSm/z (M+H): calculated 451.1, observed 451.3.

Step 2:(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)-trans-(6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methanaminehydrochloride To a stirred solution of a trans mixture(R)—N-((5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methylpropane-2-sulfinamide(0.20 g, 0.44 mmol) in MeOH (5 ml) at 20° C. was added HCl (2.2 ml, 6.7mmol). The resulting mixture was stirred at 20° C. for 1 hour. Then thesolvent was evaporated under reduced pressure, and the resulting cruderesidue was purified by reverse phase HPLC (90:10 to 5:95; watercontaining 0.1% TFA: acetonitrile containing 0.1% TFA) to give the titlecompound. LRMS m/z (M+H): calculated 347.1, observed 347.3.

Step 3: Examples 60A and 60B To a stirred solution of(5-fluoro-6-(trifluoromethyl)pyridin-2-yl)(6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methanaminehydrochloride (13 mg, 0.035 mmol) in DMF (1 ml) at 20° C. was added CDI(7.1 mg, 0.044 mmol). The mixture was stirred at 20° C. for 30 minutes,and then (R)-3-methylpiperazin-2-one (4.0 mg, 0.035 mmol) was added. Theresulting mixture was stirred at 20° C. for 2 hours and then purified byreverse phase HPLC (95:5 to 5:95; water containing 0.1% TFA:acetonitrile containing 0.1% TFA) to give a mixture of isomers, whichwas further separated by SFC (Chiral ART Cellulose-SJ column, 3 cm×25cm, 5 um, 10% MeOH (0.1% DEA) @ 80 g/min and 100 Bar) to give Examples60A (first eluted peak) and 60B (second eluted peak).

Example 60A: LRMS m/z (M+H): calculated 486.4, observed 487.4. ¹H NMR(500 MHz, Methanol-d4) δ (ppm): 7.86-7.77 (m, 1H), 7.68 (dd, J=8.6, 3.5Hz, 1H), 4.71 (d, J=10.0 Hz, 1H), 4.52 (q, J=6.7, 6.3 Hz, 1H), 4.29 (d,J=10.7 Hz, 1H), 4.02 (d, J=13.4 Hz, 1H), 3.80 (d, J=6.7 Hz, 1H),3.48-3.37 (m, 2H), 3.27-3.15 (m, 2H), 2.97 (d, J=7.3 Hz, 1H), 2.34-2.23(m, 1H), 1.78 (d, J=12.9 Hz, 1H), 1.52-1.44 (m, 1H), 1.41-1.35 (m, 4H).

Example 60B: LRMS m/z (M+H): calculated 486.4, observed 487.4. ¹H NMR(500 MHz, Methanol-d4) δ (ppm): 7.87-7.76 (m, 1H), 7.68 (dd, J=8.7, 3.5Hz, 1H), 4.76 (d, J=9.2 Hz, 1H), 4.54 (q, J=7.0 Hz, 1H), 4.08-4.01 (m,1H), 3.85-3.75 (m, 1H), 3.66-3.55 (m, 1H), 3.38-3.32 (m, 2H), 3.29-3.19(m, 2H), 2.33-2.23 (m, 1H), 2.15 (d, J=13.0 Hz, 1H), 1.93-1.84 (m, 1H),1.58 (qd, J=13.0, 3.8 Hz, 1H), 1.46 (td, J=12.5, 3.6 Hz, 1H), 1.41 (d,J=7.1 Hz, 3H).

Example 61(S)—N—((S)-(3-chloro-2,4-difluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-2-(fluoromethyl)-3-oxopiperazine-2-d-1-carboxamide

To a solution of(S)-(3-chloro-2,4-difluorophenyl)((trans)-3-(trifluoromethyl)-cyclobutyl)-methanamineoxalate (Intermediate 3, 50 mg, 0.17 mmol) in DMF (1 ml) at 25° C. wasadded CDI (54 mg, 0.33 mmol). The mixture was stirred at 25° C. for 30minutes, and then (S)-3-(fluoromethyl)piperazin-2-one-3-d (27 mg, 0.20mmol) was added. The reaction mixture was stirred at 25° C. for 1 hour,then purified by reverse phase HPLC (Boston Green ODS column, (58:42 to28:72; water (0.1% TFA):MeCN) to give the title compound. LRMS m z(M+Na): calculated 481.1, observed 481.0. ¹H NMR δ (ppm) (400 MHz,Chloroform-d): 7.28-7.32 (m, 1H), 7.07-7.12 (m, 1H), 5.08 (d, J=11.2 Hz,1H), 4.91 (dd, J=48.0, 9.2 Hz, 1H), 4.65 (dd, J=48.0, 10.0 Hz, 1H),4.03-4.07 (m, 1H), 3.27-3.33 (m, 1H), 2.85-2.87 (m, 1H), 2.37-2.38 (m,1H), 2.23-2.24 (m, 1H), 2.02-2.04 (m, 1H), 1.94-1.98 (m, 2H).

Example 62A, 62B, 62C, 62D (R)—N—((R orS)-(3-chloro-2,4-difluorophenyl)((R orS)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide (62A),(R)—N—((R or S)-(3-chloro-2,4-difluorophenyl)((S orR)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide (62B),(R)—N—((S or R)-(3-chloro-2,4-difluorophenyl)((R orS)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide (62C),(R)—N—((S or R)-(3-chloro-2,4-difluorophenyl)((S orR)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide (62D)

Step 1: N-methoxy-N-methylchromane-3-carboxamide To a solutionchromane-3-carboxylic acid (1.0 g, 5.6 mmol) in DMF (20 ml) at 0° C.were added DIEA (2.9 ml, 17 mmol) and HATU (4.3 g, 11 mmol). Theresulting mixture was stirred at 0° C. for 30 minutes, thenN,O-dimethylhydroxylamine hydrochloride (0.82 g, 8.4 mmol) was added.The resulting mixture was stirred at 20° C. for 2 hours. Then thesolvent was removed under reduced pressure and the resulting residue wasdissolved in water (20 mL) and EtOAc (15 mL). The organic layer wasseparated, and the aqueous layer was extracted with EtOAc (10 ml×3). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by silica gel chromatography, eluting with 50%EtOAc/hexane to give the title compound. LRMS m/z (M+H): calculated222.1, observed 222.3.

Step 2: (3-chloro-2,4-difluorophenyl)(chroman-3-yl)methanone To asolution of 1-bromo-3-chloro-2,4-difluorobenzene (0.99 g, 4.3 mmol) inTHF (4 ml) at 0° C. was added i-PrMgCl (2 M in THF, 2.0 ml, 4.1 mmol).The mixture was warmed to 18° C. and stirred for 2 h. To the reactionmixture was added a solution of N-methoxy-N-methylchromane-3-carboxamide(0.30 g, 1.4 mmol) in THF (2 ml) at 18° C. The reaction was stirred at18° C. for 2 h, then quenched with saturated NH₄Cl solution (10 mL) andextracted with EtOAc (10 mL×2). The combined organic layers were washedwith brine (15 mL), dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby preparative TLC (eluting with petroleum ether/ethyl acetate=10/1) togive the title compound. LRMS m/z (M+H): calculated 309.0, observed309.2.

Step 3: (3-chloro-2,4-difluorophenyl)(chroman-3-yl)methanamine Ammoniaacetate (0.64 g, 8.3 mmol) and NaBH₃CN (69 mg, 1.1 mmol) were added to asolution of (3-chloro-2,4-difluoro-phenyl)(chroman-3-yl)methanone (0.17g, 0.55 mmol) in EtOH (3 ml) and acetic acid (0.6 ml) in a microwavevial. The reaction mixture was stirred and heated at 130° C. for 10minutes in a microwave reactor. The reaction mixture was concentrated toremove most of the EtOH, treated with 2 N NaOH until the pH >10. Themixture was then extracted with EtOAc (2×20 mL). The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure to give the title compound. LRMS m/z (M+H): calculated 310.1,observed 310.2.

Step 4: Example 62A, 62B, 62C, 62D To a solution of(3-chloro-2,4-difluorophenyl)(chroman-3-yl)methanamine (0.15 g) in DMF(1 ml) at 18° C. was added CDI (157 mg, 0.969 mmol). The resultingmixture was stirred at 18° C. for 10 minutes, then a solution of(R)-3-methylpiperazin-2-one (66 mg, 0.58 mmol) in DMF (0.5 ml) wasadded. The reaction mixture was stirred at 18° C. for 1 h and thenpurified by reverse phase HPLC (Boston Green ODS, (70:30 to 40:60; water(0.1% TFA):MeCN), to give 2 peaks, which were further purified byreverse phase HPLC (Phenomenex Synergi C18, 57:43 to 37:63 water (0.1%TFA):MeCN) to give the title compounds.

Example 62A: LRMS m/z (M+H): calculated 450.1, observed 450.1. 1H NMR(500 MHz, METHANOL-d4) δ (ppm): 7.38-7.44 (m, 1H), 7.02-7.18 (m, 4H),6.80-6.85 (m, 1H), 6.72 (d, J=8.09 Hz, 1H), 4.95-5.00 (m, 1H), 4.52 (q,J=7.02 Hz, 1H), 4.02 (br d, J=13.58 Hz, 1H), 3.88 (br d, J=9.61 Hz, 1H),3.69 (dd, J=7.48, 10.83 Hz, 1H), 3.32-3.37 (m, 1H), 3.19-3.27 (m, 2H),3.10 (br dd, J=5.19, 16.33 Hz, 1H), 2.80 (dd, J=7.40, 16.40 Hz, 1H),2.59 (dt, J=2.75, 7.63 Hz, 1H), 1.38 (d, J=7.02 Hz, 3H).

Example 62B: LRMS m/z (M+H): calculated 450.1, observed 450.2. 1H NMR(500 MHz, METHANOL-d4) δ (ppm): 7.35-7.41 (m, 1H), 7.09-7.15 (m, 2H),7.04 (t, J=7.78 Hz, 1H), 6.90 (d, J=7.48 Hz, 1H), 6.73-6.81 (m, 2H),5.00 (dd, J=8.16, 10.76 Hz, 1H), 4.56 (q, J=7.07 Hz, 1H), 4.40 (br d,J=10.83 Hz, 1H), 3.97-4.08 (m, 2H), 3.34 (br d, J=3.51 Hz, 1H),3.19-3.29 (m, 3H), 2.56-2.63 (m, 1H), 2.47-2.54 (m, 1H), 2.35-2.43 (m,1H), 2.35-2.43 (m, 1H), 1.40 (d, J=7.02 Hz, 3H).

Example 62C: LRMS m/z (M+H): calculated 450.1, observed 450.1. 1H NMR(500 MHz, METHANOL-d4) δ (ppm): 7.35 (dt, J=6.18, 8.20 Hz, 1H), 7.13(dt, J=1.53, 8.62 Hz, 1H), 7.04 (t, J=7.63 Hz, 1H), 6.89 (br d, J=7.17Hz, 1H), 6.73-6.81 (m, 2H), 4.98 (br d, J=10.99 Hz, 1H), 4.50 (q, J=6.97Hz, 1H), 4.39-4.44 (m, 1H), 3.98-4.07 (m, 2H), 3.33-3.37 (m, 1H),3.16-3.28 (m, 3H), 2.61 (br d, J=2.44 Hz, 1H), 2.47-2.53 (m, 1H),2.35-2.43 (m, 1H), 1.38 (d, J=7.02 Hz, 3H)

Example 62D: LRMS m/z (M+H): calculated 450.1, observed 450.2. 1H NMR(500 MHz, METHANOL-d4) δ (ppm): 7.42 (dt, J=6.10, 8.24 Hz, 1H), 7.14(dt, J=1.53, 8.62 Hz, 1H), 7.02-7.09 (m, 2H), 6.83 (dt, J=0.99, 7.44 Hz,1H), 6.73 (d, J=8.09 Hz, 1H), 4.98 (d, J=10.83 Hz, 1H), 4.55 (q, J=7.02Hz, 1H), 3.98-4.07 (m, 1H), 3.89 (dd, J=1.37, 10.99 Hz, 1H), 3.69 (dd,J=7.55, 10.91 Hz, 1H), 3.32-3.36 (m, 1H), 3.18-3.27 (m, 2H), 3.09 (dd,J=5.19, 16.33 Hz, 1H), 2.81 (dd, J=7.48, 16.33 Hz, 1H), 2.52-2.63 (m,1H), 1.42 (d, J=7.02 Hz, 3H).

Example 63A and 63B (R orS)—N—((S)-(3-chloro-2,4-difluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-3-oxo-2-(trifluoromethyl)piperazine-1-carboxamide(63A) and (S orR)—N—((S)-(3-chloro-2,4-difluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-3-oxo-2-(trifluoromethyl)piperazine-1-carboxamide(63B)

Step 1: ethyl 2-(((benzyloxy)carbonyl)amino)-3,3,3-trifluoropropanoateTo a solution of ethyl 2-amino-3,3,3-trifluoropropanoate hydrochloride(0.50 g, 2.4 mmol) and NaHCO₃(0.37 g, 9.6 mmol) in DCM (3 ml) and water(2 ml) at 0° C. was added benzyl chloroformate (0.41 ml, 2.9 mmol). Thereaction mixture stirred for 12 hours at 20° C., then the mixture wasdiluted with water and extracted with EtOAc. The combined organic layerswere washed with water, brine, dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure. The resulting residue waspurified by flash silica gel chromatography, eluting with 30% ethylacetate/petroleum ether to give the title compound. LRMS m/z (M+H):calculated 306.1, observed 306.2.

Step 2: benzyl(3-((2,2-dimethoxyethyl)amino)-1,1,1-trifluoro-3-oxopropan-2-yl)carbamateTo a solution of 2,2-dimethoxyethan-1-amine (0.52 g, 4.9 mmol) in DCM(6.5 ml) at 0° C. was added trimethylaluminum (2.5 ml, 4.9 mmol). Thereaction mixture was stirred for 10 minutes at 0° C., then a solution ofethyl 2-(((benzyloxy)carbonyl)amino)-3,3,3-trifluoropropanoate (0.50 g,1.6 mmol) in DCM (6.5 ml) was added. The reaction mixture was stirredfor 3 hours at 20° C., then quenched with 0.1N HCl (10 ml) and extractedwith CH₂Cl₂ (2×10 mL). The combined organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated to give the title compound.

LRMS m/z (M-OCH₃): calculated 333.1, observed 333.2.

Step 3: benzyl3-oxo-2-(trifluoromethyl)-3,4-dihydropyrazine-1(2H)-carboxylate To asolution of TFA (3.5 ml) and water (1.5 ml) at 5° C. was addedbenzyl(3-((2,2-dimethoxyethyl)amino)-1,1,1-trifluoro-3-oxopropan-2-yl)carbamate(0.60 g). The reaction mixture was stirred at 20° C. for 12 h. Then themixture was slowly added to stirring cooled (5° C.) saturated aqueousNa₂CO₃ (20 mL) to keep the pH >8. The mixture was then extracted withEtOAc (20 mL×2). The combined organic layers were dried over by Na₂SO₄,filtered and concentrated. The resulting residue was purified by silicagel chromatography, eluting with petroleum ether/ethyl acetate from 1/1to 0/1 to give the title compound. ¹H NMR (400 MHz, CD30D) δ (ppm):7.30-7.44 (m, 5H), 6.32-6.43 (m, 1H), 5.55-5.74 (m, 1H), 5.14-5.28 (m,2H), 4.66-4.76 (m, 1H), 3.68-3.85 (m, 2H).

Step 4: 3-(trifluoromethyl)piperazin-2-one A solution of benzyl3-oxo-2-(trifluoromethyl)-3,4-dihydropyrazine-1(2H)-carboxylate (0.16 g,0.53 mmol) in MeOH (8 ml) was pumped through an H-Cube™ flowhydrogenator (30° C. at 1 MPa) fitted with a 5 mol % Pd/C catalystcolumn at a flow rate of 1 ml/min. The eluted phase was concentratedunder reduced pressure to give title compound. ¹H NMR (500 MHz, CD₃OD) δ4.03-4.08 (m, 2H), 3.07-3.09 (m, 2H), 2.90-3.02 (m, 2H).

Step 5: Examples 63A and 63B To a stirred solution of(S)-(3-chloro-2,4-difluorophenyl)-((trans)-3-(trifluoromethyl)cyclobutyl)methanamineoxalate (Intermediate 3, 50 mg, 0.17 mmol) in DMF (0.5 ml) at 20° C. wasadded di(1H-imidazol-1-yl)methanone (60 mg, 0.37 mmol). The reactionmixture was stirred at 20° C. for 10 minutes, then3-(trifluoromethyl)piperazin-2-one (51 mg, 0.30 mmol) was added. Themixture was stirred at 20° C. for 0.5 hours, and then purified byreverse phase HPLC (59:41 to 39:61; water containing 0.1% TFA:acetonitrile) to give a mixture of isomers, which was further separatedby SFC (DAICEL CHIRALPAK AD-H, 250 mm×30 mm, 5 um, 20% IPA) to giveExamples 63A (first eluted peak) and 63B (second eluted peak).

Example 63A: LRMS m/z (M+H): calculated 494.1, observed 494.1. ¹H NMR(400 MHz, CD₃OD) δ (ppm): 7.25-7.38 (m, 1H), 7.10 (d, J=8.8 Hz, 1H),5.30 (q, J=8.4 Hz, 1H), 5.12 (d, J=11.2 Hz, 1H), 4.04 (d, J=12.8 Hz,1H), 3.32-3.45 (m, 3H), 2.97-3.14 (m, 1H), 2.92 (s, 1H), 2.38 (s, 1H),2.15-2.30 (m, 1H), 1.89-2.11 (m, 2H).

Example 63B: LRMS m/z (M+H): calculated 494.1, observed 494.1. ¹H NMR(400 MHz, CD₃OD) δ (ppm): 7.29-7.37 (m, 1H), 7.22 (d, J=6.8 Hz, 1H),7.04-7.16 (m, 1H), 5.26-5.38 (m, 1H), 5.03-5.12 (m, 1H), 4.06 (d, J=10.4Hz, 1H), 3.31-3.43 (m, 3H), 3.03 (s, 1H), 2.89 (s, 1H), 2.36 (s, 1H),2.15-2.27 (m, 1H), 1.94-2.08 (m, 2H).

Example 64(R)—N—((S)-(3-chloro-2,4-difluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-2-(hydroxymethyl)-3-oxopiperazine-1-carboxamide

Step 1: Benzyl(R)-(1-((2,2-dimethoxyethyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamateTo a solution of ((benzyloxy)carbonyl)-D-serine (3.0 g, 13 mmol),2,2-dimethoxyethanamine (2.0 g, 19 mmol) and 4-methylmorpholine (2.2 ml,20 mmol) in MeCN (30 ml) at 15° C. was added propylphosphonic anhydride(16 g, 25 mmol, 50% in EtOAc solution). The reaction mixture was stirredat 15° C. for 30 minutes, then the reaction mixture was quenched withbrine (20 mL) and extracted with EtOAc (20 mL×3). The combined organiclayers were washed with aqueous HCl (20 mL, 1 N), saturated aqueousNaHCO₃(80 mL), dried over Na₂SO₄, and filtered. The filtrate wasconcentrated under reduced pressure to give the title compound, whichwas used in the next step without further purification.

Step 2: benzyl(R)-2-(hydroxymethyl)-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate To amixture of TFA (7.0 ml) and water (3.0 ml) at 5° C. was added benzyl(R)-(1-((2,2-dimethoxy-ethyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate(1.5 g). The reaction was stirred at 15° C. for 12 h, then the reactionmixture was added slowly to stirring cooled (5° C.) saturated aqueousNa₂CO₃ (20 mL) to keep the pH >8. The mixture was extracted with EtOAc(20 mL×2). The combined organic layers were dried over by Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by silica gel chromatography, eluting with 50-100% ethylacetate/petroleum ether gradient to give the title compound. ¹H NMR (400MHz, CD₃OD) δ (ppm): 7.25-7.47 (m, 5H), 6.28-6.44 (m, 1H), 5.54-5.77 (m,1H), 5.18-5.28 (m, 2H), 4.65-4.77 (m, 1H), 3.68-3.86 (m, 2H).

Step 3: (R)-3-(hydroxymethyl)piperazin-2-one A solution of benzyl(R)-2-(hydroxymethyl)-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate (0.50g, 1.9 mmol) in MeOH (8 ml) was pumped through an H-Cube™ flowhydrogenator (30° C. at 1 MPa) fitted with a 5 mol % Pd/C catalystcolumn at a flow rate of 1 ml/min. The eluted phase was concentratedunder reduced pressure to give the title compound. ¹H NMR (400 MHz,CD₃OD) δ (ppm): 3.89-3.97 (m, 1H), 3.77-3.86 (m, 1H), 3.47 (d, J=9.6 Hz,1H), 3.34-3.43 (m, 1H), 3.28 (t, J=3.6 Hz, 1H), 3.19 (d, J=12.8 Hz, 1H),2.90-3.12 (m, 1H).

Step 4: Example 64 To a stirred solution of(S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)methanamineoxalate (Intermediate 3, 30 mg, 0.10 mmol) in DMF (1 ml) at 20° C. wasadded di(1H-imidazol-1-yl)methanone (24 mg, 0.15 mmol). The reactionmixture was stirred at 20° C. for 10 minutes, then(R)-3-(hydroxymethyl)piperazin-2-one (17 mg, 0.13 mmol) was added. Thereaction mixture was stirred at 20° C. for 30 minutes, then filtered andpurified by reverse phase HPLC (Phenomenex Synergi C18, eluting 60:40 to40:60; water containing 0.10% TFA: acetonitrile) to give the titlecompound. LRMS m/z (M+H): calculated 456.1, observed 456.1. ¹H NMR (400MHz, CD₃OD) δ (ppm): 7.32 (d, J=12.4 Hz, 1H), 7.09 (d, J=8.8 Hz, 1H),5.04 (d, J=10.8 Hz, 1H), 4.46 (d, J=9.6 Hz, 1H), 4.00-4.08 (m, 1H),3.90-4.00 (m, 2H), 3.32-3.44 (m, 2H), 3.23-3.29 (m, 1H), 2.92-3.11 (m,1H), 2.78-2.91 (m, 1H), 2.30-2.43 (m, 1H), 2.15-2.28 (m, 1H), 1.90-2.12(m, 2H).

Example of a Pharmaceutical Composition

As a specific embodiment of an oral pharmaceutical composition, a 100 mgpotency tablet is composed of 100 mg of any one of the Examples, 268 mgmicrocrystalline cellulose, 20 mg of croscarmellose sodium, and 4 mg ofmagnesium stearate. The active, microcrystalline cellulose, andcroscarmellose are blended first. The mixture is then lubricated bymagnesium stearate and pressed into tablets.

Biological Assays Qube® Assay Experimental Procedure

Compounds were tested on human NaV1.8 and NaV1.5 channels stablyexpressed in human embryo kidney (HEK) 293 cells. Sodium currentmeasurements on Qube® were conducted as follows: automated 384-wellpatch-clamp assays on the Qube® platform (Sophion Biosciences) were usedto measure the inhibition of sodium flow through human NaV1.8 and NaV1.5channels. Whole-cell voltage-clamp recordings were performed in QChips®(Sophion Biosciences) at room temperature. NaV1.8 current measurementson Qube® were obtained as follows: NaV1.8 currents were elicited with a10 second 1 Hertz (Hz) pulse train from a holding potential of −90millivolts (mV), delivered to the cells once per minute in the controlcondition (DMSO only) and after compound addition. The 1 hertz pulsetrain stimulation consisted of ten test pulses to 10 millivolt (mV) for20 milliseconds (ms), each of which was followed by a 980 millisecondrepolarization to −67 millivolts. At the end of the 10 second pulsetrain stimulation, a 5 second hyperpolarization step to −100 millivolt(mV) was used to recover NaV1.8 from fast inactivation. The peakcurrents elicited by the 1st and 10th test pulses were used to determineIC₅₀ values for resting inhibition and inactivated state inhibition.NaV1.5 current measurements on Qube® were obtained as follows: NaV1.5currents were elicited with a 20 second 3 Hertz pulse train in thecontrol condition (DMSO only) and after compound addition. The pulsetrain consisted of sixty 20 millisecond test pulses to 0 millivolt froma holding potential of −80 millivolt (mV). The average peak currentselicited by the last 3 test pulses were used to determine IC50 valuesfor NaV1.5 inhibition.

The following buffers were used for the Qube® recordings: Externalbuffer for NaV1.8 Qube® recording: 150 NaCl, 2 CaCl2, 5 KCl, 1 Mg Cl2,10 HEPES, 12 Dextrose; External buffer for Qube® NaV1.5 recording: 120N-Methyl-D-Glucamine, 40 NaCl, 1 KCl, 2.7 CaCl2, 5 HEPES, 0.5 MgCl2; andInternal buffer for Qube® recording: 120 CsF, 30 CsCl, 10 EGTA, 5 HEPES,5 NaF, 2 MgCl2.

For all Qube® experiments offline analysis was used to determine percentinhibition as a function of drug concentration. IC₅₀ values weredetermined by fitting to the Hill equation. The compounds of structuralformula I have Nav1.8 IC₅₀ values in the Qube® Assay of less than 5micromolar. Specific IC₅₀ values of the compounds of Examples 1A-58D inthe Qube® Assay are listed in Table I.

TABLE I IC₅₀ values (nM) for Examples in the Nav1.8 Qube ® Assay ExampleIC₅₀ (nM) Example IC₅₀ (nM)  1A 3.5 36B 74.61  1B 183.1 36C 58.1  2A65.5 36D 3.99  2B 410 37A 108.5  3A 14.8 37B 145.1  3B 148.2 37C 27.19 4A 89.3 37D 1.99  4B 287.8 38A 145.5  5A 40.9 38B 158.4  5B 4.2 38C87.1  6A 232.1 38D 17.9  6B 35.4 39A 816.2  7A 112.3 39B 915.9  7B 11.739C 48.5  8A 244.4 39D 8.1  8B 13.2 40A 11730  9A 46.8 40B 14460  9B 0.840C 362.3 10A 311 40D 108.5 10B 3.87 41A 31.6 11A 870.5 41B 1180 11B4.14 41C 143 12A 342.9 41D 1064 12B 11.5 42A 321.1 13A 13.4 42B 2832 13B726 42C 24.1 14A 18.5 42D 20.1 14B 359.3 43A 39.6 15A 28.3 43B 26.4 15B553 43C 3.2 16A 366 43D 21.9 16B 935.9 44A 90.5 17A 1630 44B 335.2 17B136.1 44C 172.5 18A 4.1 44D 22.74 18B 6.87 45A 283.4 18C 91.6 45B 5.2718D 83.5 46A 342.6 19A 5.75 46B 23.7 19B 3.23 47A 11.36 19C 15.69 47B61.84 19D 10.03 47C 2.66 20A 1.37 47D 36.55 20B 191.1 48A 4366 20C 9.0248B 904.1 20D 115.9 48C 312 21A 1.08 48D 515.3 21B 2.87 49A 4.46 21C59.72 49B 84.56 21D 128.1 50A 389.2 22A 2.90 50B 9.01 22B 5.89 51A 117.522C 84.49 51B 3.03 22D 85.18 52A 319.8 23 1.16 52B 11.84 24A 2629 53A538.5 24B 29.1 53B 9.06 25A 10.37 54A 1.70 25B 652.1 54B 4.18 26 6.8255A 494.1 27A 0.80 55B 26.29 27B 106.9 57C 566 28A 2.65 57D 11.96 28B191 58A 9.23 29A 8.91 58B 5.65 29B 66.45 58C 5.10 30A 280.7 58D 6.03 30B3.12 59A 2.6 31A 0.74 59B 44 31B 70.98 60A 10.1 32A 570.6 60B 51.2 32B3.93 61 0.7 33A 135.4 62A 3.2 33B 3587 62B 358.1 34A 600.8 62C 488.2 34B47.14 62D 0.8 35A 6.08 63A 1.8 35B 48.6 63B 9.1 36A 55.74 64 3.2

The scope of the claims should not be limited by the preferredembodiments set forth in the examples, but should be given the broadestinterpretation consistent with the description as a whole.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the scope of the invention. For example,effective dosages other than the particular dosages as set forth hereinabove may be applicable as a consequence of variations in responsivenessof the mammal being treated for any of the indications with thecompounds of structural formula I indicated above. The specificpharmacological responses observed may vary according to and dependingupon the particular active compounds selected or whether there arepresent pharmaceutical carriers, as well as the type of formulation andmode of administration employed, and such expected variations ordifferences in the results are contemplated in accordance with theobjects and practices of structural formula I.

1. A compound of structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein one of A and B is independently selected from the group consisting of: (1) aryl, and (2) heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted with one to five substituents selected from R^(a), and the other of A and B is independently selected from the group consisting of: (1) C₃₋₁₂cycloalkyl, (2) C₂₋₁₁cycloheteroalkyl, (3) —C₁₋₆alkyl-C₃₋₁₂cycloalkyl, (4) —C₁₋₆alkyl-C₂₋₁₁cycloheteroalkyl, (5) —C₁₋₆alkyl-O—C₃₋₁₂cycloalkyl, and (6) —C₁₋₆alkyl-O—C₂₋₁₁cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to six substituents selected from R^(b); R¹ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, (4) —C₂₋₆alkynyl, (5) —C₃₋₆cycloalkyl, (6) —C₂₋₆cycloheteroalkyl, (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (8) —(CH₂)_(t)C(O)R^(j), (9) —(CH₂)_(t)C(O)NR^(e)R^(j), (10) —(CH₂)_(n)NR^(e)C(O)R^(j), (11) —(CH₂)_(n)NR^(e)C(O)OR^(j), (12) —(CH₂)_(n)NR^(e)C(O)N(R^(e))₂, (13) —(CH₂)_(n)NR^(e)C(O)NR^(e)R^(j), (14) —(CH₂)_(n)NR^(e)S(O)_(m)R^(j), (15) —(CH₂)_(n)NR^(e)S(O)mN(R^(e))₂, (16) —(CH₂)_(n)NR^(e)S(O)mNR^(e)R^(j), and (17) —(CH₂)_(n)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(c); R² is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, (4) —C₂₋₆alkenyl, (5) —C₂₋₆alkynyl, (6) —C₃₋₆cycloalkyl, (7) —C₂₋₆cycloheteroalkyl, (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (9) —(CH₂)_(s)C(O)R^(j), (10) —(CH₂)_(s)C(O)NR^(e)R^(j), (11) —(CH₂)_(s)NR^(e)C(O)R^(j), (12) —(CH₂)_(s)NR^(e)C(O)OR^(j), (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and (18) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(d), wherein R² and R³ and the carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring, and wherein R² and R⁴ and the carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring; R³ is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, (4) —C₂₋₆alkenyl, (5) —C₂₋₆alkynyl, (6) —C₃₋₆cycloalkyl, (7) —C₂₋₆cycloheteroalkyl, (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (9) —(CH₂)_(s)C(O)R^(j), (10) —(CH₂)_(s)C(O)NR^(e)R^(j), (11) —(CH₂)_(s)NR^(e)C(O)R^(j), (12) —(CH₂)_(s)NR^(e)C(O)OR^(j), (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and (18) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(d); R⁴ is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, (4) —C₂₋₆alkenyl, (5) —C₂₋₆alkynyl, (6) —C₃₋₆cycloalkyl, (7) —C₂₋₆cycloheteroalkyl, (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (9) —(CH₂)_(s)C(O)R^(j), (10) —(CH₂)_(s)C(O)NR^(e)R^(j), (11) —(CH₂)_(s)NR^(e)C(O)R^(j), (12) —(CH₂)_(s)NR^(e)C(O)OR^(j), (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(i), and (18) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(f), and wherein R⁴ and R⁵ and the carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring; R⁵ is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, (4) —C₂₋₆alkenyl, (5) —C₂₋₆alkynyl, (6) —C₃₋₆cycloalkyl, (7) —C₂₋₆cycloheteroalkyl, (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (9) —(CH₂)_(s)C(O)R^(j), (10) —(CH₂)_(s)C(O)NR^(e)R^(j), (11) —(CH₂)_(s)NR^(e)C(O)R^(j), (12) —(CH₂)_(s)NR^(e)C(O)OR^(j), (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and (18) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(f), and wherein R⁵ and R⁷ and the carbon atoms they are attached to may form a 4-, 5- or 6-membered saturated ring; R⁶ is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, (4) —C₂₋₆alkenyl, (5) —C₂₋₆alkynyl, (6) —C₃₋₆cycloalkyl, (7) —C₂₋₆cycloheteroalkyl, (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (9) —(CH₂)_(s)C(O)R^(j), (10) —(CH₂)_(s)C(O)NR^(e)R^(j), (11) —(CH₂)_(s)NR^(e)C(O)R^(i), (12) —(CH₂)_(s)NR^(e)C(O)OR^(j), (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and (18) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(g), and wherein R⁶ and R⁷ and the carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring; R⁷ is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, (4) —C₂₋₆alkenyl, (5) —C₂₋₆alkynyl, (6) —C₃₋₆cycloalkyl, (7) —C₂₋₆cycloheteroalkyl, (8) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (9) —(CH₂)_(s)C(O)R^(j), (10) —(CH₂)_(s)C(O)NR^(e)R^(j), (11) —(CH₂)_(s)NR^(e)C(O)R^(j), (12) —(CH₂)_(s)NR^(e)C(O)OR^(j), (13) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (14) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (16) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (17) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and (18) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(g); R⁸ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₃₋₆cycloalkyl, and (4) —C₂₋₆cycloheteroalkyl, wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from halogen; R⁹ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, and (4) —C₂₋₆alkynyl, wherein each alkyl, alkenyl and alkynyl is unsubstituted or substituted with one to five substituents selected from halogen; each R^(a) is independently selected from the group consisting of: (1) CN, (2) oxo, (3) halogen, (4) —S(O)₂C₁₋₆alkyl, (5) —C₁₋₆alkyl, (6) —C₂₋₆alkenyl, (7) —C₂₋₆alkynyl, (8) —C₃₋₆cycloalkyl, (9) —C₂₋₆cycloheteroalkyl, (10) aryl, (11) heteroaryl, (12) —C₁₋₆alkyl-aryl, (13) —C₁₋₆alkyl-heteroaryl, (14) —C₁₋₆alkyl-C₃₋₆cycloalkyl, (15) —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl, (16) —C₂₋₆alkenyl-C₃₋₆cycloalkyl, (17) —C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl, (18) —C₂₋₆alkenyl-aryl, (19) —C₂₋₆alkenyl-heteroaryl, (20) —C₂₋₆alkynyl-C₃₋₆cycloalkyl, (21) —C₂₋₆alkynylC₂₋₆cycloheteroalkyl, (22) —C₂₋₆alkynyl-aryl, (23) —C₂₋₆alkynyl-heteroaryl, (24) —OH, (25) —(CH₂)_(p)—O—C₁₋₆alkyl, (26) —(CH₂)_(p) —O—C₂₋₆alkenyl, (27) —(CH₂)_(p) —O—C₂₋₆alkynyl, (28) —(CH₂)_(p) —O—C₃₋₆cycloalkyl, (29) —(CH₂)_(p) —O—C₂₋₆cycloheteroalkyl, (30) —(CH₂)_(p) —O-aryl, (31) —(CH₂)_(p) —O-heteroaryl, (32) —OC₁₋₆alkyl-C₃₋₆cycloalkyl, (33) —OC₁₋₆alkyl-C₂₋₆cycloheteroalkyl, (34) —OC₁₋₆alkyl-aryl, (35) —OC₁₋₆alkyl-heteroaryl, (36) —S(O)_(r)R^(h), (37) —C₁₋₆alkyl-S(O)_(r)R^(h), (38) —N(R^(k))₂, (39) —C(O)R^(L), and (40) —NR^(k)R^(L), wherein each R^(a) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl; each R^(b) is independently selected from the group consisting of: (1) CN, (2) oxo, (3) halogen, (4) —S(O)₂C₁₋₆alkyl, (5) —C₁₋₆alkyl, (6) —C₁₋₆alkenyl, (7) —C₂₋₆alkynyl, (8) —C₃₋₆cycloalkyl, (9) —C₂₋₆cycloheteroalkyl, (10) aryl, (11) heteroaryl, (12) —C₁₋₆alkyl-aryl, (13) —C₁₋₆alkyl-heteroaryl, (14) —C₁₋₆alkyl-C₃₋₆cycloalkyl, (15) —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl, (16) —C₂₋₆alkenyl-C₃₋₆cycloalkyl, (17) —C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl, (18) —C₂₋₆alkenyl-aryl, (19) —C₂₋₆alkenyl-heteroaryl, (20) —C₂₋₆alkynyl-C₃₋₆cycloalkyl, (21) —C₂₋₆alkynyl-C₂₋₆cycloheteroalkyl, (22) —C₂₋₆alkynyl-aryl, (23) —C₂₋₆alkynyl-heteroaryl, (24) —OH, (25) —(CH₂)_(q)—O—C₁₋₆alkyl, (26) —(CH₂)_(q)—O—C₂₋₆alkenyl, (27) —(CH₂)_(q) —O—C₂₋₆alkynyl, (28) —(CH₂)_(q) —O—C₃₋₆cycloalkyl, (29) —(CH₂)_(q) —O—C₂₋₆cycloheteroalkyl, (30) —(CH₂)_(q) —O-aryl, (31) —(CH₂)_(q) —O-heteroaryl, (32) —OC₁₋₆alkyl-C₃₋₆cycloalkyl, (33) —OC₁₋₆alkyl-C₂₋₆cycloheteroalkyl, (34) —OC₁₋₆alkyl-aryl, (35) —OC₁₋₆alkyl-heteroaryl, (36) —S(O)_(r)R^(i), (37) —C₁₋₆alkyl-S(O)_(r)R^(i), (38) —N(R^(k))₂, (39) —C(O)R^(L), and (40) —NR^(k)R^(L), wherein each R^(b) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; R^(c) is selected from: (1) —C₁₋₆alkyl, (2) OH, (3) halogen, and (4) —OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens; R^(d) is selected from: (1) —C₁₋₆alkyl, (2) OH, (3) halogen, and (4) —OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens; R^(e) is selected from: (1) hydrogen, and (2) C₁₋₆alkyl; R^(f) is selected from: (1) —C₁₋₆alkyl, (2) OH, (3) halogen, and (4) —OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens; R^(g) is selected from: (1) —C₁₋₆alkyl, (2) OH, (3) halogen, and (4) —OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens; R^(h) is selected from: (1) hydrogen, (2) C₁₋₆alkyl, (3) C₃₋₆cycloalkyl, (4) aryl, and (5) heteroaryl; R^(i) is selected from: (1) hydrogen, (2) C₁₋₆alkyl, (3) C₃₋₆cycloalkyl, (4) aryl, and (5) heteroaryl; R^(j) is selected from: (1) hydrogen, (2) C₁₋₆alkyl, (3) C₃₋₆alkenyl, (4) C₃₋₆alkynyl, (5) C₃₋₆cycloalkyl, (6) C₂₋₅cycloheteroalkyl, (7) aryl, and (8) heteroaryl; R^(k) is selected from: (1) hydrogen, and (2) C₁₋₆alkyl; R^(L) is selected from: (1) hydrogen, (2) C₁₋₆alkyl, (3) C₃₋₆cycloalkyl, (4) aryl, and (5) heteroaryl; m is independently selected from 0, 1 and 2; n is independently selected from 2, 3, 4, 5 and 6; p is independently selected from 0, 1, 2 and 3; q is independently selected from 0, 1, 2 and 3; r is independently selected from 0, 1 and 2; s is independently selected from 0, 1, 2, 3, 4, 5, and 6; and t is independently selected from 0, 1, 2, 3, 4, 5, and
 6. 2. A compound of structural Formula I:

or a pharmaceutically acceptable salt thereof, wherein one of A and B is independently selected from the group consisting of: (1) aryl, and (2) heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted with one to five substituents selected from R^(a), and the other of A and B is independently selected from the group consisting of: (1) —C₃₋₁₂cycloalkyl, (2) —C₂₋₁₁cycloheteroalkyl, (3) —C₁₋₆alkyl-C₃₋₁₂cycloalkyl, (4) —C₁₋₆alkyl-C₂₋₁₁cycloheteroalkyl, (5) —C₁₋₆alkyl-O—C₃₋₁₂cycloalkyl, and (6) —C₁₋₆alkyl-O—C₂₋₁₁cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to six substituents selected from R^(b); R¹ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, (4) —C₂₋₆alkynyl, (5) —C₃₋₆cycloalkyl, (6) —C₂₋₆cycloheteroalkyl, (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (8) —(CH₂)_(t)C(O)R^(j), (9) —(CH₂)_(t)C(O)NR^(e)R^(j), (10) —(CH₂)_(n)NR^(e)C(O)R^(i), (11) —(CH₂)_(n)NR^(e)C(O)OR^(j), (12) —(CH₂)_(n)NR^(e)C(O)N(R^(e))₂, (13) —(CH₂)_(n)NR^(e)C(O)NR^(e)R^(j), (14) —(CH₂)_(n)NR^(e)S(O)_(m)R^(j), (15) —(CH₂)_(n)NR^(e)S(O)mN(R^(e))₂, (16) —(CH₂)_(n)NR^(e)S(O)mNR^(e)R^(j), and (17) —(CH₂)_(n)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(c); R² is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, (4) —C₂₋₆alkynyl, (5) —C₃₋₆cycloalkyl, (6) —C₂₋₆cycloheteroalkyl, (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (8) —(CH₂)_(s)C(O)R^(j), (9) —(CH₂)_(s)C(O)NR^(e)R^(j), (10) —(CH₂)_(s)NR^(e)C(O)R^(j), (11) —(CH₂)_(s)NR^(e)C(O)OR^(j), (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and (17) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(d), wherein R² and R³ and the carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring, and wherein R² and R⁴ and the carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring; R³ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, (4) —C₂₋₆alkynyl, (5) —C₃₋₆cycloalkyl, (6) —C₂₋₆cycloheteroalkyl, (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (8) —(CH₂)_(s)C(O)R^(j), (9) —(CH₂)_(s)C(O)NR^(e)R^(j), (10) —(CH₂)_(s)NR^(e)C(O)R^(i), (11) —(CH₂)_(s)NR^(e)C(O)OR^(j), (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and (17) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(d); R⁴ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, (4) —C₂₋₆alkynyl, (5) —C₃₋₆cycloalkyl, (6) —C₂₋₆cycloheteroalkyl, (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (8) —(CH₂)_(s)C(O)R^(j), (9) —(CH₂)_(s)C(O)NR^(e)R^(j), (10) —(CH₂)_(s)NR^(e)C(O)R^(j), (11) —(CH₂)_(s)NR^(e)C(O)OR^(j), (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and (17) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(f), and wherein R⁴ and R⁵ and the carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring; R⁵ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, (4) —C₂₋₆alkynyl, (5) —C₃₋₆cycloalkyl, (6) —C₂₋₆cycloheteroalkyl, (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (8) —(CH₂)_(s)C(O)R^(j), (9) —(CH₂)_(s)C(O)NR^(e)R^(j), (10) —(CH₂)_(s)NR^(e)C(O)R^(j), (11) —(CH₂)_(s)NR^(e)C(O)OR^(j), (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and (17) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(f), and wherein R⁵ and R⁷ and the carbon atoms they are attached to may form a 4-, 5- or 6-membered saturated ring; R⁶ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, (4) —C₂₋₆alkynyl, (5) —C₃₋₆cycloalkyl, (6) —C₂₋₆cycloheteroalkyl, (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (8) —(CH₂)_(s)C(O)R^(j), (9) —(CH₂)_(s)C(O)NR^(e)R^(j), (10) —(CH₂)_(s)NR^(e)C(O)R^(j), (11) —(CH₂)_(s)NR^(e)C(O)OR^(j), (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and (17) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(g), and wherein R⁶ and R⁷ and the carbon atoms they are connected to can from a —C₃₋₅cycloalkyl ring; R⁷ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, (4) —C₂₋₆alkynyl, (5) —C₃₋₆cycloalkyl, (6) —C₂₋₆cycloheteroalkyl, (7) —C₁₋₆alkyl-O—C₁₋₆alkyl-, (8) —(CH₂)_(s)C(O)R^(j), (9) —(CH₂)_(s)C(O)NR^(e)R^(j), (10) —(CH₂)_(s)NR^(e)C(O)R^(j), (11) —(CH₂)_(s)NR^(e)C(O)OR^(j), (12) —(CH₂)_(s)NR^(e)C(O)N(R^(e))₂, (13) —(CH₂)_(s)NR^(e)C(O)NR^(e)R^(j), (14) —(CH₂)_(s)NR^(e)S(O)_(m)R^(j), (15) —(CH₂)_(s)NR^(e)S(O)mN(R^(e))₂, (16) —(CH₂)_(s)NR^(e)S(O)mNR^(e)R^(j), and (17) —(CH₂)_(s)NR^(e)R^(j), wherein each CH₂, alkyl, alkenyl, alkynyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from R^(g); R⁸ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₃₋₆cycloalkyl, and (4) —C₂₋₆cycloheteroalkyl, wherein each alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one to five substituents selected from halogen; R⁹ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, and (4) —C₂₋₆alkynyl, wherein each alkyl, alkenyl and alkynyl is unsubstituted or substituted with one to five substituents selected from halogen; each R^(a) is independently selected from the group consisting of: (1) CN, (2) oxo, (3) halogen, (4) —S(O)₂C₁₋₆alkyl, (5) —C₁₋₆alkyl, (6) —C₂₋₆alkenyl, (7) —C₂₋₆alkynyl, (8) —C₃₋₆cycloalkyl, (9) —C₂₋₆cycloheteroalkyl, (10) aryl, (11) heteroaryl, (12) —C₁₋₆alkyl-aryl, (13) —C₁₋₆alkyl-heteroaryl, (14) —C₁₋₆alkyl-C₃₋₆cycloalkyl, (15) —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl, (16) —C₂₋₆alkenyl-C₃₋₆cycloalkyl, (17) —C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl, (18) —C₂₋₆alkenyl-aryl, (19) —C₂₋₆alkenyl-heteroaryl, (20) —C₂₋₆alkynyl-C₃₋₆cycloalkyl, (21) —C₂₋₆alkynylC₂₋₆cycloheteroalkyl, (22) —C₂₋₆alkynyl-aryl, (23) —C₂₋₆alkynyl-heteroaryl, (24) —OH, (25) —(CH₂)_(p)—O—C₁₋₆alkyl, (26) —(CH₂)_(p) —O—C₂₋₆alkenyl, (27) —(CH₂)_(p) —O—C₂₋₆alkynyl, (28) —(CH₂)_(p) —O—C₃₋₆cycloalkyl, (29) —(CH₂)_(p) —O—C₂₋₆cycloheteroalkyl, (30) —(CH₂)_(p) —O-aryl, (31) —(CH₂)_(p) —O-heteroaryl, (32) —OC₁₋₆alkyl-C₃₋₆cycloalkyl, (33) —OC₁₋₆alkyl-C₂₋₆cycloheteroalkyl, (34) —OC₁₋₆alkyl-aryl, (35) —OC₁₋₆alkyl-heteroaryl, (36) —S(O)_(r)R^(h), (37) —C₁₋₆alkyl-S(O)_(r)R^(h), (38) —N(R^(k))₂, (39) —C(O)R^(L), and (40) —NR^(k)R^(L), wherein each R^(a) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl; each R^(b) is independently selected from the group consisting of: (1) CN, (2) oxo, (3) halogen, (4) —S(O)₂C₁₋₆alkyl, (5) —C₁₋₆alkyl, (6) —C₁₋₆alkenyl, (7) —C₂₋₆alkynyl, (8) —C₃₋₆cycloalkyl, (9) —C₂₋₆cycloheteroalkyl, (10) aryl, (11) heteroaryl, (12) —C₁₋₆alkyl-aryl, (13) —C₁₋₆alkyl-heteroaryl, (14) —C₁₋₆alkyl-C₃₋₆cycloalkyl, (15) —C₁₋₆alkyl-C₂₋₆cycloheteroalkyl, (16) —C₂₋₆alkenyl-C₃₋₆cycloalkyl, (17) —C₂₋₆alkenyl-C₂₋₆cycloheteroalkyl, (18) —C₂₋₆alkenyl-aryl, (19) —C₂₋₆alkenyl-heteroaryl, (20) —C₂₋₆alkynyl-C₃₋₆cycloalkyl, (21) —C₂₋₆alkynyl-C₂₋₆cycloheteroalkyl, (22) —C₂₋₆alkynyl-aryl, (23) —C₂₋₆alkynyl-heteroaryl, (24) —OH, (25) —(CH₂)_(q)—O—C₁₋₆alkyl, (26) —(CH₂)_(q)—O—C₂₋₆alkenyl, (27) —(CH₂)_(q) —O—C₂₋₆alkynyl, (28) —(CH₂)_(q) —O—C₃₋₆cycloalkyl, (29) —(CH₂)_(q) —O—C₂₋₆cycloheteroalkyl, (30) —(CH₂)_(q) —O-aryl, (31) —(CH₂)_(q) —O-heteroaryl, (32) —OC₁₋₆alkyl-C₃₋₆cycloalkyl, (33) —OC₁₋₆alkyl-C₂₋₆cycloheteroalkyl, (34) —OC₁₋₆alkyl-aryl, (35) —OC₁₋₆alkyl-heteroaryl, (36) —S(O)_(r)R^(i), (37) —C₁₋₆alkyl-S(O)_(r)R^(i), (38) —N(R^(k))₂, (39) —C(O)R^(L), and (40) —NR^(k)R^(L), wherein each R^(b) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; R^(c) is selected from: (1) —C₁₋₆alkyl, (2) OH, (3) halogen, and (4) —OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens; R^(d) is selected from: (1) —C₁₋₆alkyl, (2) OH, (3) halogen, and (4) —OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens; R^(e) is selected from: (1) hydrogen, and (2) C₁₋₆alkyl; R^(f) is selected from: (1) —C₁₋₆alkyl, (2) OH, (3) halogen, and (4) —OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens; R^(g) is selected from: (1) —C₁₋₆alkyl, (2) OH, (3) halogen, and (4) —OC₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to three halogens; R^(h) is selected from: (1) hydrogen, (2) C₁₋₆alkyl, (3) C₃₋₆cycloalkyl, (4) aryl, and (5) heteroaryl; R^(i) is selected from: (1) hydrogen, (2) C₁₋₆alkyl, (3) C₃₋₆cycloalkyl, (4) aryl, and (5) heteroaryl; R^(j) is selected from: (1) hydrogen, (2) C₁₋₆alkyl, (3) C₃₋₆alkenyl, (4) C₃₋₆alkynyl, (5) C₃₋₆cycloalkyl, (6) C₂₋₅cycloheteroalkyl, (7) aryl, and (8) heteroaryl; R^(k) is selected from: (1) hydrogen, and (2) C₁₋₆alkyl; R^(L) is selected from: (1) hydrogen, (2) C₁₋₆alkyl, (3) C₃₋₆cycloalkyl, (4) aryl, and (5) heteroaryl; m is independently selected from 0, 1 and 2; n is independently selected from 2, 3, 4, 5 and 6; p is independently selected from 0, 1, 2 and 3; q is independently selected from 0, 1, 2 and 3; r is independently selected from 0, 1 and 2; s is independently selected from 0, 1, 2, 3, 4, 5, and 6; and t is independently selected from 0, 1, 2, 3, 4, 5, and
 6. 3. The compound according to claim 1 wherein A is selected from the group consisting of: (1) aryl, and (2) heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted with one to five substituents selected from R^(a); or a pharmaceutically acceptable salt thereof.
 4. The compound according to claim 1 wherein A is selected from the group consisting of: (1) phenyl, (2) pyridine, and (3) thiazole, wherein phenyl, pyridine and thiazole are unsubstituted or substituted with one to five substituents selected from R^(a); or a pharmaceutically acceptable salt thereof.
 5. The compound according to claim 1 wherein A is selected from the group consisting of: (1) phenyl, and (2) pyridine, wherein phenyl and pyridine are unsubstituted or substituted with one to four substituents selected from R^(a); or a pharmaceutically acceptable salt thereof.
 6. The compound according to claim 1 wherein B is independently selected from the group consisting of: (1) —C₃₋₁₂cycloalkyl, (2) —C₂₋₁₁cycloheteroalkyl, (3) —C₁₋₆alkyl-C₃₋₁₂cycloalkyl, (4) —C₁₋₆alkyl-C₂₋₁₁cycloheteroalkyl, (5) —C₁₋₆alkyl-O—C₃₋₁₂cycloalkyl, and (6) —C₁₋₆alkyl-O—C₂₋₁₁cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to six substituents selected from R^(b); or a pharmaceutically acceptable salt thereof.
 7. The compound according to claim 1 wherein B is independently selected from the group consisting of: (1) cyclopropane, (2) cyclobutane, (3) cyclopentane, (4) cyclohexane, (5) bicyclo[3.2.1]octane, (6) bicyclo[3.1.0]hexane, (7) bicyclo[2.2.2]octane, (8) spiro[2.5]octane, (9) bicyclo[1.1.1]pentane, (10) spiro[3.3]heptane, (11) spiro[2.3]hexane, spiro[2.2]pentane, (12) piperidine, (13) tetrahydropyran, and (14) chromane, wherein B is unsubstituted or substituted with one to six substituents selected from R^(b); or a pharmaceutically acceptable salt thereof.
 8. The compound according to claim 1 wherein B is independently selected from the group consisting of: (1) cyclopropane, (2) cyclobutane, (3) cyclopentane, (4) cyclohexane, (5) bicyclo[3.2.1]octane, (6) bicyclo[3.1.0]hexane, (7) bicyclo[2.2.2]octane, (8) spiro[2.5]octane, (9) bicyclo[1.1.1]pentane, (10) spiro[3.3]heptane, (11) spiro[2.3]hexane, spiro[2.2]pentane, (12) piperidine, and (13) tetrahydropyran, wherein B is unsubstituted or substituted with one to six substituents selected from R^(b); or a pharmaceutically acceptable salt thereof.
 9. The compound according to claim 1 wherein B is independently selected from the group consisting of: (1) —C₃₋₁₂cycloalkyl, and (2) —C₂₋₁₁cycloheteroalkyl, wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to six substituents selected from R^(b); or a pharmaceutically acceptable salt thereof.
 10. The compound according to claim 1 wherein B is independently selected from the group consisting of: (1) cyclobutane, (2) cyclohexane, and (3) tetrahydropyran, wherein cyclobutane, cyclohexane and tetrahydropyran are unsubstituted or substituted with one to six substituents selected from R^(b); or a pharmaceutically acceptable salt thereof.
 11. The compound according to claim 1 wherein R¹ is selected from the group consisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, and wherein each alkyl is unsubstituted or substituted with one to five substituents selected from R^(c); or a pharmaceutically acceptable salt thereof.
 12. The compound according to claim 1 wherein R² is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, and (4) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(d); R³ is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, and (4) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(d); R⁴ is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, and (4) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(f); R⁵ is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, and (4) —C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(f); or a pharmaceutically acceptable salt thereof.
 13. The compound according to claim 1 wherein R² is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(d); R³ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(d); R⁴ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(f); R⁵ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(f); R⁶ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(g); and R⁷ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein alkyl, and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(g); or a pharmaceutically acceptable salt thereof.
 14. The compound according to claim 1 wherein R⁸ is selected from the group consisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents selected from halogen; and R⁹ is selected from the group consisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents selected from halogen; or a pharmaceutically acceptable salt thereof.
 15. The compound according to claim 1 wherein A is selected from the group consisting of: (1) aryl, and (2) heteroaryl, wherein aryl and heteroaryl are unsubstituted or substituted with one to five substituents selected from R^(a); and B is independently selected from the group consisting of: (1) —C₃₋₁₂cycloalkyl, (2) —C₂₋₁₁cycloheteroalkyl, (3) —C₁₋₆alkyl-C₃₋₁₂cycloalkyl, (4) —C₁₋₆alkyl-C₂₋₁₁cycloheteroalkyl, (5) —C₁₋₆alkyl-O—C₃₋₁₂cycloalkyl, and (6) —C₁₋₆alkyl-O—C₂₋₁₁cycloheteroalkyl, wherein alkyl, cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to six substituents selected from R^(b); or a pharmaceutically acceptable salt thereof.
 16. The compound according to claim 1 wherein R¹ is hydrogen; R², R³, R⁴ and R⁵ are deuterium or hydrogen; R⁶ and R⁷ are CH₃ or hydrogen; and R⁸ and R⁹ are hydrogen; or a pharmaceutically acceptable salt thereof.
 17. The compound according to claim 1 wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are hydrogen; or a pharmaceutically acceptable salt thereof.
 18. The compound according to claim 1 wherein each R^(a) is independently selected from the group consisting of: (1) CN, (2) oxo, (3) halogen, (4) —S(O)₂C₁₋₆alkyl, (5) —C₁₋₆alkyl, (6) —C₂₋₆alkenyl, (7) —C₃₋₆cycloalkyl, (8) —C₂₋₆cycloheteroalkyl, (9) aryl, (10) heteroaryl, (11) —OH, (12) —O—C₁₋₆alkyl, (13) —O—C₃₋₆cycloalkyl, and (14) —O—C₂₋₆cycloheteroalkyl, wherein each R^(a) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 19. The compound according to claim 1 wherein each R^(a) is independently selected from the group consisting of: (1) halogen, (2) —C₁₋₆alkyl, and (3) —O—C₁₋₆alkyl, wherein each R^(a) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 20. The compound according to claim 1 wherein each R^(a) is independently selected from the group consisting of: (1) halogen, and (2) —C₁₋₆alkyl, wherein each R^(a) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 21. The compound according to claim 1 wherein each R^(b) is independently selected from the group consisting of: (1) CN, (2) oxo, (3) halogen, (4) —S(O)₂C₁₋₆alkyl, (5) —C₁₋₆alkyl, (6) —C₁₋₆alkenyl, (7) —C₂₋₆alkynyl, (8) —C₃₋₆cycloalkyl, (9) —C₂₋₆cycloheteroalkyl, (10) aryl, (11) heteroaryl, (12) —OH, (13) —O—C₁₋₆alkyl, (14) —O—C₃₋₆cycloalkyl, and (15) —O—C₂₋₆cycloheteroalkyl, wherein each R^(b) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 22. The compound according to claim 1 wherein each R^(b) is independently selected from the group consisting of: (1) halogen, (2) —C₁₋₆alkyl, (3) —C₁₋₆alkenyl, (4) —C₃₋₆cycloalkyl, and (5) —O—C₁₋₆alkyl, wherein each R^(b) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 23. The compound according to claim 1 wherein each R^(b) is independently selected from the group consisting of: (1) halogen, and (2) —C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 24. The compound according to claim 1 wherein A is selected from the group consisting of: (1) phenyl, (2) pyridine, and (3) thiazole, wherein phenyl, pyridine and thiazole are unsubstituted or substituted with one to five substituents selected from R^(a); B is independently selected from the group consisting of: (1) cyclopropane, (2) cyclobutane, (3) cyclopentane, (4) cyclohexane, (5) bicyclo[3.2.1]octane, (6) bicyclo[3.1.0]hexane, (7) bicyclo[2.2.2]octane, (8) spiro[2.5]octane, (9) bicyclo[1.1.1]pentane, (10) spiro[3.3]heptane, (11) spiro[2.3]hexane, spiro[2.2]pentane, (12) piperidine, (13) tetrahydropyran, and (14) chromane, wherein B is unsubstituted or substituted with one to six substituents selected from R^(b); R¹ is selected from the group consisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, and wherein each alkyl is unsubstituted or substituted with one to five substituents selected from R^(c); R² is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, and (4) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(d); R³ is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, and (4) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(d); R⁴ is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, and (4) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(f); R⁵ is selected from the group consisting of: (1) hydrogen, (2) deuterium, (3) —C₁₋₆alkyl, and (4) —C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(f); R⁶ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(g); R⁷ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein alkyl, and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(g); R⁸ is selected from the group consisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents selected from halogen; R⁹ is selected from the group consisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents selected from halogen; R^(a) is independently selected from the group consisting of: (1) CN, (2) oxo, (3) halogen, (4) —S(O)₂C₁₋₆alkyl, (5) —C₁₋₆alkyl, (6) —C₂₋₆alkenyl, (7) —C₃₋₆cycloalkyl, (8) —C₂₋₆cycloheteroalkyl, (9) aryl, (10) heteroaryl, (11) —OH, (12) —O—C₁₋₆alkyl, (13) —O—C₃₋₆cycloalkyl, and (14) —O—C₂₋₆cycloheteroalkyl, wherein each R^(a) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl; and each R^(b) is independently selected from the group consisting of: (1) CN, (2) oxo, (3) halogen, (4) —S(O)₂C₁₋₆alkyl, (5) —C₁₋₆alkyl, (6) —C₁₋₆alkenyl, (7) —C₂₋₆alkynyl, (8) —C₃₋₆cycloalkyl, (9) —C₂₋₆cycloheteroalkyl, (10) aryl, (11) heteroaryl, (12) —OH, (13) —O—C₁₋₆alkyl, (14) —O—C₃₋₆cycloalkyl, and (15) —O—C₂₋₆cycloheteroalkyl, wherein each R^(b) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 25. The compound according to claim 1 wherein A is selected from the group consisting of: (1) phenyl, (2) pyridine, and (3) thiazole, wherein phenyl, pyridine and thiazole are unsubstituted or substituted with one to five substituents selected from R^(a); B is independently selected from the group consisting of: (1) cyclopropane, (2) cyclobutane, (3) cyclopentane, (4) cyclohexane, (5) bicyclo[3.2.1]octane, (6) bicyclo[3.1.0]hexane, (7) bicyclo[2.2.2]octane, (8) spiro[2.5]octane, (9) bicyclo[1.1.1]pentane, (10) spiro[3.3]heptane, (11) spiro[2.3]hexane, spiro[2.2]pentane, (12) piperidine, and (13) tetrahydropyran, wherein B is unsubstituted or substituted with one to six substituents selected from R^(b); R¹ is selected from the group consisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, and wherein each alkyl is unsubstituted or substituted with one to five substituents selected from R^(c); R² is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(d); R³ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(d); R⁴ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(f); R⁵ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(f); R⁶ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein alkyl and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(g); R⁷ is selected from the group consisting of: (1) hydrogen, (2) —C₁₋₆alkyl, and (3) —C₃₋₆cycloalkyl, wherein alkyl, and cycloalkyl is unsubstituted or substituted with one to five substituents selected from R^(g); R⁸ is selected from the group consisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents selected from halogen; R⁹ is selected from the group consisting of: (1) hydrogen, and (2) —C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with one to five substituents selected from halogen; R^(a) is independently selected from the group consisting of: (1) CN, (2) oxo, (3) halogen, (4) —S(O)₂C₁₋₆alkyl, (5) —C₁₋₆alkyl, (6) —C₂₋₆alkenyl, (7) —C₃₋₆cycloalkyl, (8) —C₂₋₆cycloheteroalkyl, (9) aryl, (10) heteroaryl, (11) —OH, (12) —O—C₁₋₆alkyl, (13) —O—C₃₋₆cycloalkyl, and (14) —O—C₂₋₆cycloheteroalkyl, wherein each R^(a) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl; and each R^(b) is independently selected from the group consisting of: (1) CN, (2) oxo, (3) halogen, (4) —S(O)₂C₁₋₆alkyl, (5) —C₁₋₆alkyl, (6) —C₁₋₆alkenyl, (7) —C₂₋₆alkynyl, (8) —C₃₋₆cycloalkyl, (9) —C₂₋₆cycloheteroalkyl, (10) aryl, (11) heteroaryl, (12) —OH, (13) —O—C₁₋₆alkyl, (14) —O—C₃₋₆cycloalkyl, and (15) —O—C₂₋₆cycloheteroalkyl, wherein each R^(b) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 26. The compound according to claim 1 wherein A is selected from the group consisting of: (1) phenyl, and (2) pyridine, wherein phenyl and pyridine are unsubstituted or substituted with one to four substituents selected from R^(a); B is independently selected from the group consisting of: (1) —C₃₋₁₂cycloalkyl, and (2) —C₂₋₁₁cycloheteroalkyl, wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to six substituents selected from R^(b); R¹ is hydrogen; R², R³, R⁴ and R⁵ are deuterium or hydrogen; R⁶ and R⁷ are CH₃ or hydrogen; R⁸ and R⁹ are hydrogen; each R^(a) is independently selected from the group consisting of: (1) halogen, (2) —C₁₋₆alkyl, and (3) —O—C₁₋₆alkyl, wherein each R^(a) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl; and each R^(b) is independently selected from the group consisting of: (1) halogen, (2) —C₁₋₆alkyl, (3) —C₁₋₆alkenyl, (4) —C₃₋₆cycloalkyl, and (5) —O—C₁₋₆alkyl, wherein each R^(b) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 27. The compound according to claim 1 wherein A is selected from the group consisting of: (1) phenyl, and (2) pyridine, wherein phenyl and pyridine are unsubstituted or substituted with one to four substituents selected from R^(a); B is independently selected from the group consisting of: (1) —C₃₋₁₂cycloalkyl, and (2) —C₂₋₁₁cycloheteroalkyl, wherein cycloalkyl and cycloheteroalkyl are unsubstituted or substituted with one to six substituents selected from R^(b); R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are hydrogen; each R^(a) is independently selected from the group consisting of: (1) halogen, (2) —C₁₋₆alkyl, and (3) —O—C₁₋₆alkyl, wherein each R^(a) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OH, C₁₋₆alkyl, and —OC₁₋₆alkyl; and each R^(b) is independently selected from the group consisting of: (1) halogen, (2) —C₁₋₆alkyl, (3) —C₁₋₆alkenyl, (4) —C₃₋₆cycloalkyl, and (5) —O—C₁₋₆alkyl, wherein each R^(b) is unsubstituted or substituted with one to six substituents selected from halogen, CF₃, OCF₃, CN, CH₂CF₃, CF₂CH₃, —C₁₋₆alkyl, and —OC₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 28. The compound according to claim 1 selected from: (1) N—((R)-3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide; (2) N—((S)-3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide; (3) N—((R)-(3-chloro-4-fluorophenyl)(8,8-difluorobicyclo[3.2.1]octan-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (4) N—((S)-(3-chloro-4-fluorophenyl)(8,8-difluorobicyclo[3.2.1]octan-3-yl)methyl)-3-oxopiperazine-1-carboxamide; (5) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(8,8-difluorobicyclo[3.2.1]octan-3-yl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (6) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(8,8-difluorobicyclo[3.2.1]octan-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (7) N—((R)-(4-chlorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide; (8) N—((R)-(4-chlorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide; (9) N—((S)-(4-chlorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide; (10) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)-cyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (11) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)-cyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (12) (R)-2-methyl-3-oxo-N—((R)-(trans-4-(trifluoromethyl)cyclohexyl)(3,4,5-trifluorophenyl)methyl)piperazine-1-carboxamide; (13) (R)-2-methyl-3-oxo-N—((S)-(trans-4-(trifluoromethyl)cyclohexyl)(3,4,5-trifluorophenyl)methyl)piperazine-1-carboxamide; (14) (2R)—N—((R)-(3-chloro-4-fluorophenyl)((1R,3s,5S)-6,6-difluorobicyclo-[3.1.0]hexan-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (15) (2R)—N—((S)-(3-chloro-4-fluorophenyl)((1R,3s,5S)-6,6-difluorobicyclo-[3.1.0]hexan-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (16) (2R)—N—((R)-(3,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (17) (2R)—N—((S)-(3,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (18) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (19) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (20) N—((R)-(3-chloro-2,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)-methyl)-3-oxopiperazine-1-carboxamide; (21) N—((S)-(3-chloro-2,4-difluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)-methyl)-3-oxopiperazine-1-carboxamide; (22) (R)—N—((R)-(3-chloro-2,4-difluorophenyl)((1R,3s,5S)-6,6-difluorobicyclo-[3.1.0]hexan-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (23) (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((1R,3s,5S)-6,6-difluorobicyclo-[3.1.0]hexan-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (24) N—((R)-(3-chloro-4-fluorophenyl)(4-(trifluoromethyl)bicyclo[2.2.2]octan-1-yl)methyl)-3-oxopiperazine-1-carboxamide; (25) N—((S)-(3-chloro-4-fluorophenyl)(4-(trifluoromethyl)bicyclo[2.2.2]octan-1-yl)methyl)-3-oxopiperazine-1-carboxamide; (26) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(4,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (27) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(4,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (28) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(4,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (29) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(4,4-difluorocyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (30) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (31) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (32) (2R)—N—((R)-(4-chlorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (33) (2R)—N—((S)-(4-chlorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (34) N—((R)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide; (35) N—((S)-(3-chloro-4-fluorophenyl)(1-(2,2,2-trifluoroethyl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide; (36) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(1-(R)-(1,1,1-trifluoropropan-2-yl)-piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide; (37) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(1-(S)-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide; (38) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(1-(R)-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide; (39) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(1-(S)-(1,1,1-trifluoropropan-2-yl)piperidin-4-yl)methyl)-3-oxopiperazine-1-carboxamide; (40) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(trans-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (41) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(trans-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (42) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(cis-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (43) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(cis-1,1-difluorospiro[2.5]octan-6-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (44) (R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (45) (R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (46) (R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (47) (R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (48) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-cyclopropylcyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (49) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-cyclopropylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (50) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-cyclopropylcyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (51) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-cyclopropylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (52) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-1,1-difluorospiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (53) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-1,1-difluorospiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (54) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-1,1-difluorospiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (55) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-1,1-difluorospiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (56) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(6,6-difluorospiro[3.3]heptan-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (57) 2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(6,6-difluorospiro[3.3]heptan-2-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (58) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(3,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (59) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(3,3-difluorocyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (60) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(3-methylenecyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (61) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(3-methylenecyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (62) N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxopiperazine-1-carboxamide; (63) (R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (64) (S)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-cyclopropyl-3-oxopiperazine-1-carboxamide; (65) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(spiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (66) (2R)—N—((S)(3-chloro-2,4-difluorophenyl)(spiro[2.3]hexan-5-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (67) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (68) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (69) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]-pentan-1yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (70) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(3-(trifluoromethyl)bicyclo-[1.1.1]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (71) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(3,3-dimethylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (72) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(3,3-dimethylcyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (73) N—((R)-(3-chloro-2,4-difluorophenyl)(3,3-dimethylcyclobutyl)methyl)-3-oxopiperazine-1-carboxamide; (74) N—((S)-(3-chloro-2,4-difluorophenyl)(3,3-dimethylcyclobutyl)methyl)-3-oxopiperazine-1-carboxamide; (75) (2R)—N—((R)-(3,3-dimethylcyclobutyl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (76) (2R)—N—((S)-(3,3-dimethylcyclobutyl)(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (77) N—((R)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-3-oxopiperazine-1-carboxamide; (78) N—((S)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-3-oxopiperazine-1-carboxamide; (79) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (80) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (81) (2R)—N—((R)-(4-fluoro-3-methylphenyl)(trans-4-(trifluoromethyl)cyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (82) (2R)—N—((S)-(4-fluoro-3-methylphenyl)(trans-4-(trifluoromethyl)cyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (83) (2R)—N—((R)-(4-fluoro-3-methylphenyl)(cis-4-(trifluoromethyl)cyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (84) (2R)—N—((S)-(4-fluoro-3-methylphenyl)(cis-4-(trifluoromethyl)cyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (85) (2R)—N—((R)-(4-chloro-3-(difluoromethyl)phenyl)(cis-4-(trifluoromethyl) cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (86) (2R)—N—((R)-(4-chloro-3-(difluoromethyl)phenyl)(trans-4-(trifluoromethyl) cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (87) (2R)—N—((S)-(4-chloro-3-(difluoromethyl)phenyl)(cis-4-(trifluoromethyl) cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (88) (2R)—N—((S)-(4-chloro-3-(difluoromethyl)phenyl)(trans-4-(trifluoromethyl) cyclohexyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (89) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(trans-3-(difluoromethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (90) (2R)—N—((R)-(3-chloro-4-fluorophenyl) (cis-3-(difluoromethoxy) cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (91) (2R)—N—((S)-(3-chloro-4-fluorophenyl) (cis-3-(difluoromethoxy) cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (92) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(trans-3-(difluoromethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (93) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (94) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-(difluoromethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (95) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-(difluoromethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (96) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(difluoromethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (97) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(trans-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (98) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)(cis-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (99) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(cis-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (100) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-methoxycyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (101) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((R)-spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (102) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((S)-spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (103) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)(R)-spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (104) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((S)-spiro[2.2]pentan-1-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (105) (2R)—N—((R)-(3-chloro-2,4-difluoro phenyl)((R)-3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (106) (2R)—N—((R)-(3-chloro-2,4-difluoro phenyl)((S)-3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (107) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((R)-(3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (108) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((S)-3,3-difluorocyclopentyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (109) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (110) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (111) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (112) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(cis-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (113) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(cis-3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (114) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(cis-3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (115) (2R)—N—((R)-(3-chloro-4-fluorophenyl)(trans-3-(2,2,2-trifluoroethoxy)-cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (116) (2R)—N—((S)-(3-chloro-4-fluorophenyl)(trans-3-(2,2,2-trifluoroethoxy)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (117) N—((R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-4-(trifluoromethyl)-cyclohexyl) methyl)-3-oxopiperazine-1-carboxamide; (118) N—((S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-4-(trifluoromethyl)cyclo-hexyl)methyl)-3-oxopiperazine-1-carboxamide; (119) (2R)—N—((R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(4,4-difluorocyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (120) (2R)—N—((S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(4,4-difluorocyclohexyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (121) (2R)—N—((R or S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(cis-3-(trifluoromethyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (122) (2R)—N—((R or S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoro-methyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (123) (2R)—N—((S or R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoro-methyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (124) (2R)—N—((S or R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(cis-3-(trifluoro-methyl)-cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (125) (2R)—N—((R or S)-1-(3-chloro-4-fluorophenyl)-1-(cis-3-(trifluoromethyl)-cyclobutyl)-ethyl)-2-methyl-3-oxopiperazine-1-carboxamide; (126) (2R)—N—((R or S)-1-(3-chloro-4-fluorophenyl)-1-(trans-3-(trifluoromethyl)-cyclobutyl)-ethyl)-2-methyl-3-oxopiperazine-1-carboxamide; (127) (2R)—N—((S or R)-1-(3-chloro-4-fluorophenyl)-1-(cis-3-(trifluoromethyl)-cyclobutyl)-ethyl)-2-methyl-3-oxopiperazine-1-carboxamide; (128) (2R)—N—((S or R)-1-(3-chloro-4-fluorophenyl)-1-(trans-3-(trifluoromethyl)-cyclobutyl)-ethyl)-2-methyl-3-oxopiperazine-1-carboxamide; (129) (2R)—N—((R)-(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)-cyclo-butyl) methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (130) (2R)—N—((S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)-cyclo-butyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (131) ((2R)—N—((R)-(2-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)-cyclo-butyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (132) (2R)—N—((S)-(2-fluoro-4-(trifluoromethoxy)phenyl)(trans-3-(trifluoromethyl)-cyclo-butyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (133) (2R)—N—((R)-(4-fluoro-3-(trifluoromethyl)phenyl)(trans-3-(trifluoromethyl)cyclo-butyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (134) (2R)—N—((S)-(4-fluoro-3-(trifluoromethyl)phenyl)(trans-3-(trifluoromethyl)-cyclo-butyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (135) N—((R)-(4-fluoro-3-(trifluoromethyl)phenyl)(trans-3-(trifluoro methyl)-cyclobutyl)-methyl)-3-oxopiperazine-1-carboxamide; (136) N—((S)-(4-fluoro-3-(trifluoromethyl)phenyl)(trans-3-(trifluoro methyl)cyclobutyl)-methyl)-3-oxopiperazine-1-carboxamide; (137) (2R)—N—((R)-(3-chloro-2-fluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (138) (2R)—N—((S)-(3-chloro-2-fluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (139) (2R)—N—((R)-(3-chloro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl) cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (140) (2R)—N—((S)-(3-chloro-4-(trifluoromethoxy)phenyl)(3-(trifluoromethyl) cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (141) (2R)-2-methyl-3-oxo-N-((trans-4-(trifluoromethyl)cyclohexyl)((R)-2-(trifluoro-methyl)thiazol-4-yl)methyl)piperazine-1-carboxamide; (142) (2R)-2-methyl-3-oxo-N-((trans-4-(trifluoromethyl) cyclohexyl)((S)-2-(trifluoro-methyl)thiazol-4-yl)methyl)piperazine-1-carboxamide; (143) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((3R, 6R)-6-(trifluoromethyl)-tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (144) (2R)—N—((R)-(3-chloro-2,4-difluorophenyl)((3S, 6S)-6-(trifluoromethyl)-tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (145) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((3R, 6R)-6-(trifluoromethyl)-tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (146) (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((3S, 6S)-6-(trifluoromethyl)-tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (147) (2R)—N—(R)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (148) (2R)—N—(R)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (149) (2R)—N—(S)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (150) (2R)—N—(S)-(3-chloro-2,4-difluorophenyl)(trans-2-(trifluoromethyl)cyclopropyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (151) (2R)—N—((R or S)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)-cyclopentyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (152) (2R)—N—((R or S)-(3-chloro-2,4-difluorophenyl)(cis-3-(trifluoromethyl)-cyclopentyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (153) (2R)—N—((R or S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)-cyclopentyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; and (154) (2R)—N—((R or S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclopentyl)-methyl)-2-methyl-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.
 29. The compound according to claim 1 selected from: (1) (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-5,5,6,6-d4-1-carboxamide; (2) (S)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-methyl-3-oxopiperazine-5,5,6,6-d4-1-carboxamide; (3) (2R)—N-((1(R or S))-(4-fluoro-3-(trifluoromethyl)phenyl)-trans-(6-(trifluoromethyl)-tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (4) (2R)—N-((1(R or S))-(4-fluoro-3-(trifluoromethyl)phenyl)-trans-(6-(trifluoromethyl)-tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (5) (S)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-(fluoromethyl)-3-oxopiperazine-2-d-1-carboxamide; (6) (R)—N—((R)-(3-chloro-2,4-difluorophenyl)((R)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; s (7) (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((R)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (8) (R)—N—((R)-(3-chloro-2,4-difluorophenyl)((S)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (9) (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((S)-chroman-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; (10) (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxo-2-(trifluoromethyl)piperazine-1-carboxamide; (11) (S)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-3-oxo-2-(trifluoromethyl)piperazine-1-carboxamide; and (12) (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((1r,3S)-3-(trifluoromethyl)cyclobutyl)-methyl)-2-(hydroxymethyl)-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.
 30. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 31-35. (canceled)
 36. A method of treating or preventing a disorder, condition or disease that is responsive to the inhibition of Na_(v)1.8 channel activity in a patient in need thereof comprising administration of a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.
 37. The method of claim 36 wherein the disorder is selected from: pain disorder, a cough disorder, an acute itch disorder or chronic itch disorder.
 38. The method of claim 37 wherein the disorder is a pain disorder.
 39. The method of claim 38 wherein the pain disorder is selected from: acute pain, inflammatory pain, or neuropathic pain.
 40. The compound according to claim 1 which is (R)—N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.
 41. The compound according to claim 1 which is (R)—N—((S)-(3-chloro-2,4-difluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-5,5,6,6-d4-1-carboxamide; or a pharmaceutically acceptable salt thereof.
 42. The compound according to claim 1 which is (S)—N—((S)-(3-chloro-2,4-difluorophenyl)((trans)-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-5,5,6,6-d4-1-carboxamide; or a pharmaceutically acceptable salt thereof.
 43. The compound according to claim 1 which is N—((R)-3-chloro-4-fluorophenyl)(trans-4-(trifluoromethyl)cyclohexyl)methyl)-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.
 44. The compound according to claim 1 which is N—((S)-(3-chloro-2,4-difluorophenyl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.
 45. The compound according to claim 1 which is (2R)—N—((S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.
 46. The compound according to claim 1 which is (2R)—N—((R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(trans-3-(trifluoromethyl)cyclobutyl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof.
 47. The compound according to claim 1 which is (2R)—N—((S)-(3-chloro-2,4-difluorophenyl)((3S, 6S)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)methyl)-2-methyl-3-oxopiperazine-1-carboxamide; or a pharmaceutically acceptable salt thereof. 